Azabicyclo derivatives for treatment of urinary incontinence

ABSTRACT

The present invention relates to a method of treating urinary incontinence in mammals, including humans, using certain quinuclidine derivatives, piperidine derivatives, azanorbornane derivatives of azabiaglo and related compounds.

This is a division, of application Ser. No. 08/013,277, filed on Feb. 4,1993 now U.S. Pat. No. 5,340,826.

BACKGROUND OF THE INVENTION

The present invention relates to a method of treating or preventingurinary incontinence in mammals, including humans, using certainquinuclidine derivatives, piperidine derivatives, azanorbornanederivatives, ethylene diamine derivatives and related compounds. Thepharmaceutically active compounds employed in this invention aresubstance P receptor antagonists.

The following reference refer, collectively, to quinuclidine,piperidine, and azanorbornane derivatives and related compounds thatexhibit activity as substance P receptor antagonists: U.S. Pat. No.5,162,339, which issued on Nov. 11, 1992; U.S. patent application724,268, filed Jul. 1, 1991; PCT patent application PCT/US91/02853,filed Apr. 25, 1991; PCT patent application PCT/US 91/03369,filed May 14, 1991; PCT patent application PCT/US 91/05776, filed Aug.20, 1991; PCT patent application PCT/US 92/00113, filed Jan. 17, 1992;PCT patent application PCT/US 92/03571, filed May 5, 1992; PCT patentapplication PCT/US 92/03317, filed Apr. 28, 1992; PCT patent applicationPCT/US 92/04697, filed Jun. 11, 1992; U.S. patent application 766,488,filed Sep. 26, 1991; U.S. patent application 790,934, filed Nov. 12,1991; PCT patent application PCT/US 92/04002, filed May 19, 1992;Japanese Patent Application 065337/92, filed Mar. 23, 1992; U.S. patentapplication 932,392, filed Aug. 19, 1992; and U.S. patent application988,653, filed Dec. 10, 1992.

SUMMARY OF THE INVENTION

The present invention relates to a method of treating or preventingurinary incontinence in a mammal, including a human, comprisingadministering to said mammal an amount of a compound of the formula##STR1## wherein A is a ring system selected from phenyl, naphthyl,thienyl, quinolinyl and indolinyl, and wherein the sidechain containingNR² R³ is attached to a carbon atom of ring system A;

AA is an aryl group selected from phenyl, naphthyl, thienyl,dihydroquinolinyl and indolinyl, and wherein the sidechain containingNR² R³ is attached to a carbon atom of AA;

W¹ is hydrogen halo or (C₁ -C₆) alkyl, S--(C₁ -C₃) alkyl, halo or (C₁-C₆) alkoxy optionally substituted with from one to three fluorineatoms.

W is hydrogen, (C₁ -C₆) alkyl optionally substituted with from one tothree fluorine atoms, --S(O)_(v) --(C₁ -C₆) alkyl wherein v is zero, oneor two, halo or (C₁ -C₆) alkoxy optionally substituted with from one tothree fluorine atoms;

R is a 4, 5 or 6 membered heterocyclic ring containing from one to threeheteroatoms selected from oxygen, nitrogen and sulfur (e.g., thiazolyl,azetidinyl, pyrrolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl,isothiazolyl, imidazolyl, isoxazolyl, or oxazolyl) wherein saidheterocyclic ring may contain from zero to three double bonds and mayoptionally be substituted with one or more substituents, preferably oneor two substituents, independently selected from (C₁ -C₆) alkyloptionally substituted with from one to three fluorine atoms and (C₁-C₆) alkoxy optionally substituted with from one to three fluorineatoms;

R¹ is selected from amino, (C₁ -C₆) alkylamino, di-(C₁ -C₆) alkylamino,--S(O)_(v) --(C₁ -C₁₀)-alkyl wherein v is zero, one or two --S(O)_(v)-aryl wherein v is zero, one or two, --)-aryl, --SO₂ NR⁴ R⁵ wherein eachof R⁴ and R⁵ is, independently, (C₁ -C₆) alkyl, or R⁴ and R⁵, togetherwith the nitrogen to which they are attached, form a saturated ringcontaining one nitrogen and from 3 to 6 carbons, ##STR2## wherein one orboth of the alkyl moieties may optionally be substituted with from oneto three fluorine atoms, --N(SO₂ --(C₁ -C₁₀) alkyl)₂ and ##STR3##wherein the aryl moieties of said --S(O)_(v) -aryl, --O-aryl and##STR4## are independently selected from phenyl and benzyl and mayoptionally be substituted with from one to three substituentsindependently selected from (C₁ -C₄) alkyl, (C₁ -C₄) alkoxy and halo;

or R¹ is a group having the formula ##STR5## wherein a is 0, 1 or 2 andthe asterisk represents a position meta to the R² R³ NCH₂ side chain;

the dotted lines in formula Ib represent that one of the X-Y and Y-Zbonds may optionally be a double bond;

X is selected from ═C--, --CH₂ --, --O--, --S--, --SO--, --SO₂ --,--N(R⁴)--, --NH--, ═N--, --CH[(C₁ -C₆) alkyl]--, ═C[(C₁ -C₆) alkyl]--,--CH(C₆ H₅)-- and ═C(C₆ H₅)--;

Y is selected from C═O, C═NR⁴, C═S, ═CH--, --CH₂ --, ═C[(C₁ -C₆)alkyl]--, --CH[(C₁ -C₆) alkyl]--, ═C(C₆ H₆)--, --CH(C₆ H₅)--, ═N--,--NH--, --N(R⁴)--, ═C(halo)--, ═C(OR⁴)--, ═C(SR⁴)--, ═C(NR⁴)--, --O--,--S-- and SO₂, wherein the phenyl moieties of said ═C(C₆ H₅)-- and--CH(C₆ H₅)-- may optionally be substituted with from one to threesubstituents independently selected from trifluoromethyl and halo, andwherein the alkyl moieties of said ═[(C₁ -C₆) alkyl]-- and --CH[C₁ -C₆)alkyl]-- may optionally be substituted with from one to three fluorineatoms;

Z is selected from ═CH--, --CH₂ --, ═N--, --NH--, --S--, --N(R⁴) --,═C(C₆ H₅)--, --CH(C₆ H₅)--, ═C[(C₁ -C₆) alkyl]-- and --CH[(C₁ -C₆)alkyl]--;

or X, Y and Z, together with the two carbon atoms shared between thebenzo ring and the XYZ ring, form a fused pyridine or pyrimidine ring;

R⁴ is (C₁ -C₆) alkyl or phenyl;

R² is hydrogen or --CO₂ (C₁ -C₁₀) alkyl;

R³ is selected from ##STR6## wherein R⁶ and R¹⁰ are independentlyselected from furyl, thienyl, pyridyl, indolyl, biphenyl and phenyl,wherein said phenyl may optionally be substituted with one or twosubstituents independently selected from halo, (C₁ -C₁₀) alkyloptionally substituted with from one to three fluorine atoms, (C₁ -C₁₀)alkoxy optionally substituted with from one to three fluorine atoms,carboxy, benzyloxycarbonyl and (C₁ -C₃) alkoxy-carbonyl;

R⁷ is selected from (C₃ -C₄) branched alkyl, (C₅ -C₆) branched alkenyl,(C₅ -C₇) cycloalkyl, and the radicals named in the definition of R⁶ ;

R⁸ is hydrogen or (C₁ -C₆) alkyl;

R⁹ and R¹⁹ are independently selected from phenyl, biphenyl, naphthyl,pyridyl, benzhydryl, thienyl and furyl, and R⁹ and R¹⁹ may optionally besubstituted with from one to three substitutents independently selectedfrom halo, (C₁ -C₁₀) alkyl optionally substituted with from one to threefluorine atoms and (C₁ -C₁₀) alkoxy optionally substituted with from oneto three fluorine atoms;

Y¹ is (CH₂)₁ wherein 1 is an integer from one to three, or Y¹ is a groupof the formula ##STR7## Z¹ is oxygen, sulfur, amino, (C₁ -C₃) alkylaminoor (CH₂)_(n) wherein n is zero, one or two;

x is an integer from zero to four;

y is an integer from zero to four;

z is an integer from one to six, wherein the ring containing (CH₂)_(z)may contain from zero to three double bonds, and one of the carbons of(CH₂)_(z) may optionally be replaced by oxygen, sulfur or nitrogen;

o is two or three;

p is zero or one;

r is one, two or three;

R¹¹ thienyl, biphenyl or phenyl optionally substituted with one or twosubstituents independently selected from halo, (C₁ -C₁₀) alkyloptionally substituted with from one to three fluorine atoms and (C₁-C₁₀) alkoxy optionally substituted with from one to three fluorineatoms;

X⁴ is (CH₂)_(q) wherein q is an integer from 1 to 6, and wherein any oneof the carbon-carbon single bonds in said (CH₂)_(q) may optionally bereplaced by a carbon-carbon double bond, and wherein any one of thecarbon atoms of said (CH₂)_(q) may optionally be substituted with R¹⁴,and wherein any one of the carbon atoms of said (CH₂)_(q) may optionallybe substituted with R¹⁵ ;

m is an integer from 0 to 8, and any one of the carbon-carbon singlebonds of (CH₂)_(m), wherein both carbon atoms of such bond are bonded toeach other and to another carbon atom in the (CH₂)_(m) chain, mayoptionally be replaced by a carbon-carbon double bond or a carbon-carbontriple bond, and any one of the carbon atoms of said (CH₂)_(m) mayoptionally be substituted with R¹⁷ ;

R¹² is a radical selected from hydrogen, (C₁ -C₆) straight or branchedalkyl, (C₃ -C₇) cycloalkyl wherein one of the carbon atoms mayoptionally be replaced by nitrogen, oxygen or sulfur; aryl selected frombiphenyl, phenyl, indanyl and naphthyl; heteroaryl selected fromthienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl,triazolyl, tetrazolyl and quinolyl; phenyl-(C₂ -C₆) alkyl, benzhydryland benzyl, wherein the point of attachment on R¹² is a carbon atomunless R¹² is hydrogen, and wherein each of said aryl and heteroarylgroups and the phenyl moieties of said benzyl, phenyl-(C₂ -C₆) alkyl andbenzhydryl may optionally be substituted with one or more substituentsindependently selected from halo, nitro, (C₁ -C₁₀) alkyl optionallysubstituted with from one to three fluorine atoms, (C₁ -C₁₀) alkoxyoptionally substituted with from one to three fluorine atoms, amino,hydroxy-(C₁ -C₆) alkyl, (C₁ -C₆) alkoxy-(C₁ -C₆) alkyl, (C₁-C₆)-alkylamino, ##STR8## and wherein one of the phenyl moieties of saidbenzhydryl may optionally be replaced by naphthyl, thienyl, furyl orpyridyl;

R¹³ is hydrogen, phenyl or (C₁ -C₆) alkyl;

or R¹² and R¹³, together with the carbon to which they are attached,form a saturated carbocyclic ring having from 3 to 7 carbon atomswherein one of said carbon atoms that is neither the point of attachmentof the spiro ring nor adjacent to it may optionally be replaced byoxygen, nitrogen or sulfur;

R¹⁴ and R¹⁵ are each independently selected from hydrogen, hydroxy,halo, amino, oxo (═O), cyano, hydroxy-(C₁ -C₆) alkyl, (C₁ -C₆)alkoxy-(C₁ -C₆), (C₁ -C₆) alkylamino, ##STR9## and the radicals setforth in the definition of R¹² ;

R¹⁶ is ##STR10## NHCH₂ R¹⁸, SO₂ R¹⁸, GR²⁰ CO₂ H or one of the radicalsset forth in any of the definitions of R¹², R¹⁴ and R¹⁵ ;

R¹⁷ is oximino (═NOH) or one of the radicals set forth in any of thedefinitions of R¹², R¹⁴ and R¹⁵ ; and

R¹⁸ is (C₁ -C₆) alkyl, hydrogen, phenyl or phenyl (C₁ -C₆) alkyl;

G is selected from the group consisting of CH₂, nitrogen, oxygen, sulfurand carbonyl;

R²⁰ is a monocyclic or bicyclic heterocycle selected from the groupconsisting of pyrimidinyl, benzoxazolyl,2,3-dihydro-3-oxobenzisosulfonazol-2-yl, morpholin-1-yl,thiomorpholin-1-yl, benzofuranyl, benzothienyl, indolyl, isoindolyl,isoquinolinyl, furyl, pyridyl, isothiazolyl, oxazolyl, triazolyl,tetrazolyl, quinolyl, thiazolyl, thienyl, and groups of the formulae##STR11## wherein B and D are selected from carbon, oxygen, andnitrogen, and at least one of B and D is other than carbon; E is carbonor nitrogen; n is an integer from 1 to 5; and any one of the carbons ofthe (CH₂)_(n) or (CH₂)_(n+1) may be optionally substituted with (C₁ -C₆)alkyl or (C₂ -C₆) spiro alkyl, and either any two of the carbon atoms ofsaid (CH₂)_(n) and (CH₂)_(n+1) may be bridged by a one or two carbonatom linkage, or any one pair of adjacent carbons of said (CH₂)_(n) and(CH₂)_(n+1) may form, together with from one to three carbon atoms thatare not members of the carbonyl containing ring, a (C₃ -C₅) fusedcarbocyclic ring;

with the proviso that (a) when m is 0, one of R¹⁶ and R¹⁷ is absent andthe other is hydrogen, (b) when R³ is a group of the formula VIII, R¹⁴and R¹⁵ cannot be attached to the same carbon atom, (c) when R¹⁴ and R¹⁵are attached to the same carbon atom, then either each of R¹⁴ and R¹⁵ isindependently selected from hydrogen, fluoro, (C₁ -C₆) alkyl,hydroxy-(C₁ -C₆) alkyl and (C₁ -C₆) alkoxy-(C₁ -C₆) alkyl, or R¹⁴ andR¹⁵, together with the carbon to which they are attached, form a (C₃-C₆) saturated carbocyclic ring that forms a spiro compound with thenitrogen-containing ring to which they are attached; (d) R¹² and R¹³cannot both be hydrogen; (e) when R¹⁴ or R¹⁵ is attached to a carbonatom of X⁴ or (CH₂)_(y) that is adjacent to the ring nitrogen, then R¹⁴or R¹⁵, respectively, must be a substitutent wherein the point ofattachment is a carbon atom; and (f) neither R¹⁴, R¹⁵, R¹⁶ nor R¹⁷ canform a ring with R¹³ ;

or a pharmaceutically acceptable salt thereof, effective in treating orpreventing such condition.

The fused bicyclic nucleus of compounds of the formula Ib to which W andthe --CN₂ NR² R³ sidechain are attached may be, but is not limited toone of the following groups: benzoxazolyl, benzthiazolyl,benzimidazolyl, benzisoxazolyl, benzoisothiazolyl, indazolyl, indolyl,isoquinolinyl, benzofuryl, benzothienyl, oxindolyl, benzoxazolinonyl,benzthiazolinonyl, benzimidazolinonyl, benzimidazoliniminyl,dihydrobenzothienyl-S, S-dioxide, benztriazolyl, benzthiadiazolyl,benzoxadiazolyl, and quinazolinyl.

Preferred embodiments of this invention include methods of treating orpreventing urinary incontinence in a mammal, including a human, thatcomprise administering to said mammal an amount of a compound as definedin paragraphs (1) through (46) below, that is effective in treating orpreventing such condition.

(1) A compound of the formula Ia or Ib wherein the substituents atpositions "2" and "3" of the nitrogen containing ring of R³ are in a cisconfiguration . (When R³ is a group of the formula VII or VIII, "a cisconfiguration", as used herein, means that the non-hydrogen substituentat position "3" is cis to R¹²).

(2) A compound of the formula Ia wherein R³ is a group of the formulaIII, VII or IX; R² is hydrogen, A is phenyl or indolinyl; W is (C₁ -C₃)alkoxy optionally substituted with from one to five fluorine atoms; andR is thiazolyl, imidazolyl, thiadiazolyl, pyrrolyl or oxazolyl, and Rmay optionally be substituted with one or two (C₁ -C₃) alkyl moieties.

(3) A compound of the formula Ib wherein R³ is a group of the formulaIII, VII or IX; R² is hydrogen; the fused bicyclic ring system to whichW and the --CH₂ NR² R³ sidechain are attached is benzoxazolyl,benzisoxazolyl, benzthiazolyl or benzimidazolyl; and W is (C₁ -C₆)alkoxy optionally substituted with from one to five fluorine atoms.

(4) A compound as defined in paragraph 1, 2 or 3 above wherein: (a) R³is a group of the formula III and R⁹ is benzhydryl; (b) R³ is a group ofthe formula VII, R¹² is phenyl, each of R¹³, R¹⁴, R¹⁵ and R¹⁶ ishydrogen, m is zero and X⁴ is --(CH₂)₃ --; or (c) R³ is a group of theformula IX, r is two and R¹⁹ is benzhydryl.

(5) a compound of the formula Ia wherein: (a) R³ is a group of theformula III wherein the substitutents at positions "2" and "3" of thenitrogen containing ring are in the cis configuration, R⁹ is benzhydryland A is phenyl; or (b) R³ is a group of the formula VII wherein R¹² andthe substituent at position "3" of the nitrogen containing ring are inthe cis configuration, A is phenyl, R¹² is phenyl, each of R², R¹³, R¹⁴,R¹⁵ and R¹⁶ is hydrogen, m is zero, W is methoxy or isopropoxy, X⁴ is--(CH₂)₃ -- and R is thiazolyl, imidazolyl, pyrrolyl, oxazolyl orthiadiazolyl.

(6) A compound of the formula Ib wherein R³ is a group of the formula IXwherein the substituents at positions "2" and "3" of the nitrogencontaining ring are in the cis configuration, R¹⁹ is benzhydryl, r istwo and the fused bicyclic ring system to which W and the --CH₂ NR² R³sidechain are attached is benzisoxazolyl or benzthiazolyl.

(7) a compound of the formula Ib wherein R³ is a group of the formulaIX, R¹⁹ is benzhydryl, the fused bicyclic ring system to which W and the--CH₂ NR² R³ sidechain are attached is benzisoxazolyl, and W is methoxy.

(8) A compound of the formula Ib wherein R³ is a group of the formulaVII, R¹² is phenyl, each of R¹³, R¹⁴, R¹⁵ and R¹⁶ is hydrogen, m iszero, X⁴ is --(CH₂)₃ --, and the fused bicyclic ring system to which Wand the --CH₂ NR² R³ sidechain are attached is benzothiazolyl,benzoxazolyl or benzimidazolyl.

(9) A compound of the formula Ia wherein R³ is a group of the formulaVII, each of R¹³, R¹⁴, R¹⁵ and R¹⁶ is hydrogen, m is zero, X⁴ is--(CH₂)₃ --, A is phenyl, W is methoxy, and R is selected fromthiazolyl, imidazolyl, thiadiazolyl and isoxazolyl.

(10) A compound of the formula Ia or Ib that is selected from:

(2S,3S)-3-[2-methoxy-5-(2-thiazolyl)benzyl]amino-2-phenylpiperidine;

(2S,3S)-3-[5-(2-imidazolyl)-2-methoxybenzyl]amino-2-phenylpiperidine;

(2S,3S)-3-[2-methoxy-5-(2-oxopyrrolidinyl)benzyl]amino-2-phenylpiperidine;

(2S,3S)-3-[2-methoxy-5-(4-methyl-2-thiazolyl)benzyl]-amino-2-phenylpiperidine;

(2S,3S)-3-[2-methoxy-5-(1,2,3-thiadiazol-4-yl)benzyl]-amino-2-phenylpiperidine;

(2S,3S)-(6-methoxy-2-methyl-benzothiazol-5-ylmethyl)-(2-phenylpiperidin-3-yl)amine;

(2S,3S)-[5-(2,5-dimethyl-pyrrol-1-yl)-2-methoxybenzyl]-(2-phenylpiperidin-3-yl)amine;

(2S,3S)-3-[2-methoxy-5-(5-oxazolyl)benzyl]amino-2-phenylpiperdine;

(2S,3S)-(6-methoxy-2-methyl-benzoxazol-5-ylmethyl)-(2-phenyl-piperidin-3-yl)-amine;and

(1SR,2SR,3SR,4RS)-3-[6-methoxy-3-methylbenzisoxazol-5-yl]methylamino-2-benzhydrylazanorbornane.

(11) A compound of the formula Ic, wherein R³ is a group of the formulaII, III, VII or IX; R² is hydrogen; ring AA is phenyl or indolinyl; W¹is (C₁ -C₃) alkoxy optionally substituted with from one to threefluorine atoms; and R¹ is S(O)_(v) -(C₁ -C₁₀) alkyl wherein v is zero,one or two, S(O)_(v) -aryl wherein v is zero, one or two, --O-aryl,##STR12## wherein one or both of the alkyl moieties may optionally besubstituted with from one to three fluorine atoms, --N(SO₂ -(C₁ -C₁₀)alkyl)₂ or ##STR13## wherein said aryl is phenyl or benzyl and mayoptionally be substituted with from one to three substituentsindependently selected from (C₁ -C₄) alkyl, (C₁ -C₄) alkoxy and halo.

(12) A compound as defined in paragraph 11 above, wherein R³ is a groupof the formula II, o is two, and each R⁶ and R⁷ is phenyl.

(13) A compound as defined in paragraph 11 above, wherein R³ is a groupof the formula VII, each of R¹³, R¹⁴, R¹⁵ and R¹⁶ is hydrogen, R¹² isphenyl, m is zero and X⁴ is --(CH₂)₃ --.

(14) A compound as defined in paragraph 11 above, wherein R³ is a groupof the formula IX, R¹⁹ is benzhydryl and r is two.

(15) A compound as defined in paragraph 11 above, wherein R³ is a groupof the formula III, R⁸ is other than hydrogen and R⁹ is benzyhydryl.

(16) A compound to the formula Ic wherein the substituents at positions"2" and "3" of the nitrogen containing ring are in the cisconfiguration.

(17) A compound of the formula Ic wherein R³ is a group of the formulaII wherein the substituents at positions "2" and "3" of the nitrogencontaining ring are in the cis configuration, o is two, each of R⁶ andR⁷ is phenyl and ring AA is phenyl or indolinyl.

(18) A compound of the formula Ic wherein R³ is a group of the formulaIII wherein the substituents at positions "2" and "3" of the nitrogencontaining ring are in the cis configuration, R⁸ is other than hydrogen,R⁹ is benzhydryl and ring AA is phenyl.

(19) A compound of the formula Ic wherein R³ is a group of the formulaVII wherein R¹² and the substituent at position "3" of the nitrogencontaining ring are in the cis configuration, ring AA is phenyl, R¹² isphenyl, each of R², R¹³, R¹⁴, R¹⁵ and R¹⁶ is hydrogen, m is zero, X⁴ is--(CH₂)₂ -- or --(CH₂)₃ -- and R¹ is selected from S(O)_(v) -(C₁ -C₁₀)alkyl wherein v is zero, one or two and ##STR14## di-(C₁ -C₆)alkylamino.

(20) A compound as defined in paragraph 19 above, wherein X⁴ is --(CH₂)₂-- and W¹ is (C₁ -C₆) alkoxy optionally substituted with from one tothree fluorine atoms.

(21) A compound as defined in paragraph 19 above, wherein X⁴ is --(CH₂)₃-- and W¹ is (C₁ -C₆) alkoxy optionally substituted with from one tothree fluorine atoms.

(22) A compound of the formula Ic, wherein R³ is a group of the formulaIX wherein the substituents at positions "2" and "3" of the nitrogencontaining ring are in the cis configuration, r is two and R¹⁹ isbenzhydryl.

(23) A compound as defined in paragraph 22 above, wherein ring AA isphenyl, W¹ is (C₁ -C₅) alkoxy optionally substituted with from one tothree fluorine atoms and R¹ is selected from --S(O)_(v) -(C₁ -C₁₀) alkylwherein v is zero, one or two, di-(C₁ -C₆) alkylamino and ##STR15##

(24) A compound as defined in paragraph 15 above, wherein ring AA isphenyl, W¹ is (C₁ -C₆) alkoxy optionally substituted with from one tothree fluorine atoms, and R¹ is selected from --S(O)_(v) -(C₁ -C₁₀)alkyl wherein v is zero, one or two and ##STR16##

(25) A compound as defined in paragraph 15 above, wherein ring AA isphenyl, W¹ is (C₁ -C₆) alkoxy optionally substituted with from one tothree fluorine atoms, and R¹ is selected from amino, (C₁ -C₆) alkylaminoor di-(C₁ -C₆) alkylamino.

(26) A compound as defined in paragraph 12 above, wherein ring AA isphenyl, W¹ is (C₁ -C₆) alkoxy optionally substituted with from one tothree fluorine atoms, and R¹ is selected from --S(O)_(v) -(C₁ -C₁₀)alkyl wherein v is zero, one or two, and ##STR17##

(27) A compound as defined in paragraph 12 above, wherein ring AA isphenyl, W¹ is (C₁ -C₆) alkoxy optionally substituted with from one tothree fluorine atoms, and R¹ is selected from amino, (C₁ -C₆) alkylaminoor di-(C₁ -C₆) alkylamino.

(28) A compound as defined in paragraph 24 above, wherein W¹ is attachedat the "2" position of ring AA and R¹ is attached at the "5" position ofring AA, relative to the point of attachment of the NR² R³ containingside chain.

(29) A compound as defined in paragraph 25 above, wherein W¹ is attachedat the "2" position of ring AA and R¹ is attached at the "5" position ofring AA, relative to the point of attachment of the NR² R³ containingside chain.

(30) A compound as defined in paragraph 26 above, wherein W¹ is attachedat the "2" position of ring AA and R¹ is attached at the "5" position ofring AA, relative to the point of attachment of the NR² R³ containingside chain.

(31) A compound as defined in paragraph 27 above, wherein W¹ is attachedat the "2" position of ring AA and R¹ is attached at the "5" position ofring AA, relative to the point of attachment of the NR² R³ containingside chain.

(32) A compound as defined in paragraph 13 above, wherein ring AA isphenyl, W¹ is selected from isopropoxy, OCF₃, OCH₃, OCHF₂ and OCH₂ CF₃,and R¹ is selected from --(O)_(v) -(C₁ -C₁₀) alkyl wherein v is zero,one or two, and (C₁ -C₁₀) alkyl-N-SO₂ -(C₁ -C₁₀) alkyl.

(33) A compound selected from the group consisting of:

(2S,3S)-N-(2-methoxy-5-methylsulfonylphenyl)-methyl-2-diphenylmethyl-1-azabicyclo[2.2.2]octan-3-amine;

(2S,3S)-N-(2-methoxy-5-methylthiophenyl)methyl-2-diphenylmethyl-1-azabicyclo[2.2.2]octan-3-amine;

(2S,3S)-N-(2-methoxy-5-dimethylaminophenyl)methyl-2-diphenylmethyl-1-azabicyclo[2.2.2]octan-3-amine; and

(2S,3S)-N-(5-trifluoroacetylamino-2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo[2.2.2]octan-3-amine.

(34) a compound of the formula Ic, wherein R³ is a group of the formulaVII, m is zero, each of R¹³, R¹⁵, R¹⁶ and R¹⁷ is hydrogen, R¹² isphenyl, R¹⁴ is ##STR18## ring AA is phenyl, W¹ is (C₁ -C₃) alkoxy and R¹is selected from (C₁ -C₅) alkyl, --SCH₃, SO₂ CH₃, SOCH₃, (C₁ -C₆)alkylamino and di-(C₁ -C₆) alkyl-amino.

(35) A compound of the formula Ic, having the formula ##STR19##

(36) A compound of the formula Id wherein R⁶, R¹⁰, R¹¹ and R¹³ arephenyl, R⁸ is hydrogen, R⁹ is phenyl optionally substituted withchlorine, fluorine, (C₁ -C₆) alkyl optionally substituted with from oneto three fluorine atoms or (C₁ -C₆) alkoxy optionally substituted withfrom one to three fluorine atoms, m is 0 and n is 3 or 4.

(37) A compound of the formula Id that is selected from the groupconsisting of:

(2S,3S)-3-(5-tert-butyl-2-methoxybenzyl)amino-2-(3-trifluoromethoxyphenyl)piperidine;

(2S,3S)-3-(2-isopropoxy-5-trifluoromethoxybenzyl)amino-2-phenyl-piperidine;

(2S,3S)-3-(2-ethoxy-5-trifluoromethoxybenzyl)amino-2-phenyl-piperidine;

(2S,3S)-3-(2-methoxy-5-trifluoromethoxybenzyl)-amino-2-phenylpiperidine;

(2S,3S)-3(-5-tert-butyl-2-trifluoromethoxybenzyl)amino-2-phenylpiperidine;

2-(diphenylmethyl)-N-(2-methoxy-5-trifluoromethoxy-phenyl)methyl-1-azabicyclo[2.2.2]octan-3-amine;

(2S,3S)-3-[5-chloro-2-(2,2,2-trifluoroethoxy)-benzyl]amino-2-phenylpiperidine;

(2S,3S)-3-(5-tert-butyl-2-trifluoromethoxybenzyl)amino-2-phenylpiperidine;

(2S,3S)-3-(2-isopropoxy-5-trifluoromethoxybenzyl)amino-2-phenylpiperidine;

(2S,3S)-3-(2-difluoromethoxy-5-trifluoromethoxybenzyl)-amino-2-phenylpiperidine;

(2S,3S)-2-phenyl-3-[2-(2,2,2-trifluoroethoxybenzyl)-aminopiperidine; and

(2S,3S)-2-phenyl-3-(2-trifluoromethoxybenzyl)]aminopiperidine.

(38) A compound of the formula Id, wherein R³ is a group of the formulaII wherein o is two or three and each of R⁶ and R⁷ is phenyl orsubstituted phenyl.

(39) A compound of the formula Id, wherein R³ is a group of the formulaIII, R⁸ is hydrogen and R⁹ is phenyl or substituted phenyl.

(40) A compound of the formula Id, wherein R³ is a group of the formulaIV wherein l is one or two and each of R¹⁰ and R¹¹ is phenyl orsubstituted phenyl.

(41) A compound of the formula Id, wherein R³ is a group of the formulaV wherein n is zero or one and each of R¹⁰ and R¹¹ is phenyl orsubstituted phenyl.

(42) A compound of the formula Id, wherein R³ is a group of the formulaVI wherein p is one and each of R¹⁰ and R¹¹ are phenyl or substitutedphenyl.

(43) A compound of the formula Id, wherein R³ is a group of the formulaVII wherein q is two, three or four, m is zero and R¹² is phenyl orsubstituted phenyl.

(44) A compound of the formula Id, wherein R³ is a group of the formulaVIII wherein y is zero, x is zero or one, z is three or four, m is zeroand R¹² is phenyl or substituted phenyl.

(45) A compound of the formula Id wherein R³ is a group of the formulaVII, R⁶, R¹⁴, R¹³ R¹⁶ and R¹⁵ are hydrogen, R¹² is phenyl, X¹ is2-methoxy, X² and X³ are independently selected from hydrogen, chlorine,fluorine, methyl, (C₁ -C₆) alkoxy and trifluoromethane, m is 0 and q is3 or 4.

(46) A compound of the formula Id wherein R³ is a group of the formulaVII and said compound is selected from the group consisting of:

cis-3-(2-chlorobenzylamino)-2-phenylpiperidine;

cis-3-(2-trifluoromethylbenzylamino)-2-phenyl-piperidine;

cis-3-(2-methoxybenzylamino)-2-(2-fluorophenyl)-piperidine;

cis-3-(2-methoxybenzylamino)-2-(2-chlorophenyl)-piperidine;

cis-3-(2-methoxybenzylamino)-2-(2-methylphenyl)-piperidine;

cis-3-(2-methoxybenzylamino)-2-(3-methoxyphenyl)-piperidine;

cis-3-(2-methoxybenzylamino)-2-(3-fluorophenyl)-piperidine;

cis-3-(2-methoxybenzylamino)-2-(3-chlorophenyl)-piperidine;

cis-3-(2-methoxybenzylamino)-2-phenylpiperidine;

cis-3-(2-methoxybenzylamino)-2-(3-methylphenyl)-piperidine;

cis-3-(2-methoxybenzylamino)-2-(4-fluorophenyl)-piperidine;

cis-3-(2-methoxybenzylamino)-2-(3-thienyl)-piperidine;

cis-3-(2-methoxybenzylamino)-2-phenylazacyclo-heptane;

3-(2-methoxybenzylamino)-4-methyl-2-phenyl-piperidine;

3-(2-methoxybenzylamino)-5-methyl-2-phenyl-piperidine;

3-(2-methoxybenzylamino)-6-methyl-2-phenyl-piperidine;

(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine;

(2S,3S)-1-(5-carboethoxypent-1-yl)-3-(2-methoxybenzyl-amino)-2-phenylpiperidine;

(2S,3S)-1-(6-hydroxy-hex-1-yl)-3-(2-methoxybenzyl-amino)-2-phenylpiperidine;

(2S,3S)-1-(4-hydroxy-4-phenylbut-1-yl)3-(2-methoxy-benzylamino)2-phenylpiperidine;

(2S,3S)-1-(4-oxo-4-phenylbut-1-yl)-3-(2-methoxybenzyl-amino)-2-phenylpiperidine;

(2S,3S)-1-(5,6-dihydroxyhex-1-yl)-3-(2-methoxybenzyl-amino)-2-phenylpiperidine;

cis-3-(5-fluoro-2-methoxybenzylamino)-2-phenyl-piperidine;

(2S,3S)-1-[4-(4-fluorophenyl)-4-oxobut-1-yl]-3-(2-methoxybenzylamino)-2-phenylpiperidine;

(2S,3S)-1-[4-[4-fluorophenyl)-4-hydroxybut-1-yl]-3-(2-methoxybenzylamion)-2-phenylpiperidine;

cis-3-(2-methoxy-5-methylbenzylamino)-2-phenyl-piperidine;

(2S,3S)-1-(4-benzamidobut-1-yl)-3-(2-methoxybenzyl-amino)-2-phenylpiperidine;

cis-3-(2-methoxynaphth-1-ylmethylamino)-2-phenyl-piperidine;

(2S,3S)-3-(2-methoxybenzylamino)-1-(5-N-methyl-carboxamidopent-1-yl)-2-phenylpiperidine;

(2S,3S)-1-(4-cyanobut-1-yl)-3-(2-methoxybenzylamino)-2-phenylpiperidine;

(2S,3S)-1-[4-(2-naphthamido)but-1-yl]-3-(2-methoxy-benzylamino)-2-phenylpiperidine;

(2S,3S)-1-(5-benzamidopent-1-yl)-3-(2-methoxybenzyl-amino)-2-phenylpiperidine;

(2S,3S)-1-(5-aminopent-1-yl)-3-(2-methoxybenzylamino)-2-phenylpiperidine;

(2S,3S)-3-(5-chloro-2-methoxybenzylamino)-2-phenylpiperidine;

(2S,3S)-3-(2,5-dimethoxybenzylamino)-2-phenylpiperidine;

cis-3-(3,5-difluoro-2-methoxybenzylamino)-2-phenyl-piperidine;

cis-3-(4,5-difluoro-2-methoxybenzylamino)-2-phenyl-piperidine;

cis-3-(2,5-dimethoxybenzylamino)-1-[4-(4-fluorophenyl)-4-oxobut-1yl]-2-phenylpiperidine;

cis-3-(5-chloro-2-methoxybenzylamino)-1-(5,6-dihydroxyhex-1yl)-2-phenylpiperidine;

cis-1-(5,6-dihydroxyhex-1-yl)-3-(2,5-dimethoxy-benzylamino)-2-phenylpiperidine;

cis-2-phenyl-3-[-2(prop-2-yloxy)benzylamino]piperidine;

cis-3-(2,5-dimethoxybenzyl)amino-2-(3-methoxy-phenyl) piperidinehydrochloride;

cis-3-(5-chloro-2-methoxybenzyl)amino-2-(3-methoxy-phenyl) piperidinedihydrochloride;

cis-3-(5-chloro-2-methoxybenzyl)amino-2-(3-chloro-phenyl) piperidinedihydrochloride;

3-(2-methoxybenzylamino)-2,4-diphenylpiperidine;

cis-3-(2-methoxybenzylamino)-2-phenylpyrrolidine;

(2S,3S)-3-(5-ethyl-2-methoxybenzyl)amino-2-phenyl-piperidine;

(2S,3S)-3-(5-n-butyl-2-methoxybenzyl)amino-2-phenyl-piperidine;

(2S,3S)-3-(2-methoxy-5-n-propylbenzyl)amino-2-phenyl-piperidine;

(2S,3S)-3-(5-isopropyl-2-methoxybenzyl)amino-2-phenyl-piperidine;

(2S,3S)-3-(5-s-butyl-2-methoxybenzyl)amino-2-phenyl-piperidine;

(2S,3S)-3-(5-t-butyl-2-methoxybenzyl)amino-2-phenyl-piperidine; and

(2S,3S)-3-(2-methoxy-5-phenylbenzyl)amino-2-phenyl-piperidine.

(47) A compound of the formula Id, wherein R³ is a group of the formulaII or III and said compound is selected from the group consisting of:

(2S,3S)-N-(5-isopropyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo[2.2.2]octan-3-amine;

(2S,3S)-N-(5-tert-butyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo[2.2.2]octan-3-amine;

(2S,3S)-N-(5-methyl-2-methoxyphenyl)methyl-2-diphenyl-methyl-1-azabicyclo[2.2.2]octan-3-amine;

(2S,3S)-N-(5-ethyl-2-methoxyphenyl)methyl-2-diphenyl-methyl-1-azabicyclo[2.2.2]octan-3-amine;

(2S,3S)-N-(5-isopropyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo[2.2.2]octan-3-amine;

(2S,3S)-N-(5-sec-butyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo[2.2.2]octan-3-amine; and

(2S,3S)-N-(5-n-propyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo[2.2.2]octan-3-amine.

This invention also relates to a method of treating or preventingurinary incontinence in a mammal, including a human, comprisingadministering to said mammal an amount of a compound having the formula##STR20## wherein W is Y or X(CH₂)_(n) ;

Y is optionally substituted (C₁ -C₆) alkyl, optionally substituted (C₂-C₆) alkenyl or optionally substituted (C₃ -C₈) cycloalkyl;

X is optionally substituted (C₁ -C₆) alkoxy, CONR¹ R², CO₂ R¹, CHR¹ OR²,CHR¹ NR² R³, COR¹, CONR¹ OR² or optionally substituted aryl, whereinsaid aryl is selected from phenyl, naphthyl, pyridyl, quinolyl, thienyl,furyl, phenoxyphenyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl andpyrazolyl; and n is an integer from zero to six;

Ar¹, Ar² and Ar³ are each, independently, optionally substituted aryl,wherein said aryl is selected from phenyl, naphthyl, pyridyl, quinolyl,thienyl, furyl, phenoxyphenyl, oxazolyl, tetrazolyl, thiazolyl,imidazolyl and pyrazolyl;

and R¹, R² and R³ are independently selected from hydrogen, optionallysubstituted (C₁ -C₆) alkyl, optionally substituted (C₁ -C₆) alkoxy,optionally substituted (C₃ -C₈) cycloalkyl, optionally substituted aryl,wherein said aryl is selected from phenyl, naphthyl, pyridyl, quinolyl,thienyl, furyl, phenoxyphenyl, oxazolyl, tetrazolyl, thiazolyl,imidazolyl and pyrazolyl; and optionally substituted (C₁ -C₅)heterocyclic groups, wherein said heterocyclic groups are selected frompyrrolidino, piperidino, morpholino, piperazinyl and thiamorpholino;

and wherein the substituents on the foregoing substituted alkyl,alkenyl, cycloalkyl and alkoxy groups are independently selected fromhalo, nitro, amino, (C₁ -C₄) alkyl, (C₁ -C₄) alkoxy, trifluoromethyl andtrifluoromethoxy;

and wherein the substituents on the foregoing substituted heterocyclicgroups are attached to an oxygen or nitrogen atom on the ring and areindependently selected from oxygen and (C₁ -C₄) alkyl;

and wherein the substituents on said substituted Ar¹ groups areindependently selected from (C₁ -C₆) alkyl optionally substituted withfrom one to three halo groups, (C₁ -C₆) alkoxy optionally substitutedwith from one to three halo groups, (C₁ -C₆) alkylsulfonyl, (C₁-C₆)alkylsulfonylamino, and di-(C₁ -C₆) alkylamino wherein one or bothof the alkyl groups may be optionally substituted with a (C₁ -C₆)alkylsulfonyl, or (C₁ -C₆) alkylsulfinyl group;

and wherein the substituents on said substituted Ar² and Ar³ groups areindependently selected from (C₁ -C₄) alkyl, (C₁ -C₄) alkoxy, (C₁ -C₄)alkylthio, (C₁ -C₄) alkylsulfinyl, di-(C₁ -C₄) alkylamino,trifluoromethyl and trifluoromethoxy;

and wherein the substituents on said substituted (C₁ -C₅) heterocyclicgroups are independently selected from oxygen and (C₁ -C₄) alkyl; or apharmaceutically acceptable salt of such compound, effective in treatingor preventing such condition.

Preferred embodiments of this invention including methods of treating orpreventing urinary incontinence in a mammal, including a human, thatcomprise administering to said mammal an amount of a compound as definedin paragraphs (48) through (53) below, that is effective in treating orpreventing such condition.

(48) A compound of the formula X, wherein W is X(CH₂)_(n).

(49) A compound of the formula X, wherein W is Y.

(50) A compound of the formula X, wherein Ar¹ is substituted aryl and Wis Y.

(51) A compound of the formula X, wherein Ar¹ is mono-, di- ortri-substituted phenyl and W is Y.

(52) A compound of the formula X, wherein Ar¹ is phenyl disubstituted atthe 2- and 5-positions and W is Y.

(53) A compound of the formula X, wherein Ar¹ is paramethoxyphenyl, eachof Ar² and Ar³ is phenyl and W is Y.

(54) A compound of the formula X that is selected from the groupconsisting of:

(3R,4S,5S,6S)-N,N-diethyl-5-(5-isopropyl-2-methoxy-benzylamino6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxamide;

(3R,4S,5S,6S)-N,N-diethyl-5-(2,5-dimethoxybenzylamino)-6-diphenylmethyl1-azabicyclo[2.2.2]octane-3-carboxamide;

(3R,4S,5S,6S)-5-(5-isopropyl-2-methoxybenzylamino)-6-diphenylmethyl1-azabicyclo[2.2.2]octane-3-carboxylic acid;

(3R,4S,5S,6S)-5-(2-methoxy-2-methylthiobenzylamino)-6-diphenylmethyl1-azabicyclo[2.2.2]octane-3-carboxylic acid;

(3R,4S,5S,6S)-5-(2,5-dimethoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxylic acid;

(3R,4S,5S,6S)-5-(2-methoxy-5-methylbenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxylic acid;

(3R,4S,5S,6S)-5-(5-ethyl-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxylic acid;

(3R,4S,5S,6S)-5-(2-methoxyl-5-n-propylbenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxylic acid;

(3R,4S,5S,6S)-5-(5-sec-butyl-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxylic acid;

(3R,4S,5S,6S)-5-(5-aminosulfonylmethyl-2-methoxybenzylamino6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxylic acid;

(3R,4S,5S,6S)-5-(2-methoxy-5-methylsulfinylbenzyl-amino)6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxylic acid;

(3R,4S,5S,6S)-5-(2-methoxy-5-trifluoromethoxybenzyl-amino)6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxylic acid;

(3R,4S,5S,6S)-5-(2-methoxy-5-methylsulfonylbenzyl-amino)6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxylic acid;

(3R,4S,5S,6S)-5-(5-dimethylamino-2-methoxybenzylamino)6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxylic acid;

(3R,4S,5S,6S)-5-(5-isopropyl-2-methoxybenzylamino)6-diphenylmethyl-1-azabicyclo[2.2.2]octane-2-carboxylic acid;

(3R,4S,5S,6S)-5-(2-methoxy-5-methylthiobenzylamino)6-diphenylmethyl-1-azabicyclo[2.2.2]octane-2-carboxylic acid;

(3r,4S,5S,6S)-5-(2,5-dimethoxybenzylamino)-6-diphenylmethyl1-azabicyclo[2.2.2]octane-2-carboxylic acid;

(3R,4S,5S,6S)-5-(2-methoxy-5-methylbenzylamino)-6-diphenylmethyl1-azabicyclo[2.2.2]octane-2-carboxylic acid;

(3R,4S,5S,6S)-5-(5-ethyl-2-methoxybenzylamino)-6-diphenylmethyl1-azabicyclo[2.2.2]octane-2-carboxylic acid;

(3R,4S,5S,6S)-5-(2-methoxyl-5-n-propylbenzylamino)-6-diphenylmethyl1-azabicyclo[2.2.2]octane-2-carboxylic acid;

(3R,4S,5S,6S)-5-(5-sec-butyl-2-methoxybenzylamino)-6-diphenylmethyl1-azabicyclo[2.2.2]octane-2-carboxylic acid;

(3R,4S,5S,6S)-5-(5-aminosulfonylmethyl-2-methoxybenzylamino)6-diphenylmethyl-1-azabicyclo[2.2.2]octane-2-carboxylic acid;

(3r,4s,5S,6S)-5-(2-methoxy-5-methylsulfinylbenzylamino)-6-diphenylmethyl1-azabicyclo[2.2.2]octane-2-carboxylic acid;

(3R,4S,5S,6S)-5-(2-methoxy-5-trifluoromethoxybenzylamino)-6-diphenylmethyl1-azabicyclo[2.2.2]octane-2-carboxylic acid;

(3R,4S,5S,6S)-5-(2-methoxy-5-methylsulfonylbenzylamino)-6-diphenylmehtyl1-azabicyclo[2.2.2]octane-2-carboxylic acid; and

(3R,4S,5S,6S)-5-(5-dimethylamino-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-2-carboxylicacid.

This invention also relates to a method of treating or preventingurinary incontinence in a mammal, including a human, comprisingadministering to said mammal an amount of a compound having the formula##STR21## wherein R¹ is selected from hydrogen, (C₁ -C₆) straight orbranched alkyl, (C₃ -C₇) cycloalkyl wherein one of the carbon atoms mayoptionally be replaced by nitrogen, oxygen or sulfur; aryl selected fromphenyl, biphenyl, indanyl and naphthyl; heteroaryl selected fromthienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl,triazolyl, tetrazolyl and quinolyl; phenyl (C₂ -C₆) alkyl, benzhydryland benzyl, wherein each of said aryl and heteroaryl groups and thephenyl moieties of said benzyl, phenyl (C₂ -C₆) alkyl and benzhydryl mayoptionally be substituted with one or more substituents independentlyselected from halo, nitro, (C₁ -C₆) alkyl optionally substituted withfrom one to three fluorine atoms, (C₁ -C₆) alkoxy, amino, trihaloalkoxy(e.g., trifluoromethoxy), ##STR22## and wherein one of the phenylmoieties of said benzhydryl may optionally be replaced by naphthyl,thienyl, furyl or pyridyl;

R³ is aryl selected from phenyl and naphthyl; heteroaryl selected fromindanyl, thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl,isoxazolyl, triazolyl, tetrazolyl and quinolyl; and cycloalkyl having 3to 7 carbon atoms wherein one of said carbon atoms may optionally bereplaced by nitrogen, oxygen or sulfur; wherein each of said aryl andheteroaryl groups may optionally be substituted with one or moresubstituents, and said (C₃ -C₇) cycloalkyl may optionally be substitutedwith one or two substituents, each of said substituents beingindependently selected from halo, nitro, (C₁ -C₆) alkyl optionallysubstituted with from one to three fluorine atoms, (C₁ -C₆) alkoxyoptionally substituted with from one to three fluorine atoms, amino,phenyl, trihaloalkoxy (e.g., trifluoromethoxy), ##STR23##

one of R⁵ and R⁶ is hydrogen and the other is selected fromhydroxymethyl, hydrogen, (C₁ -C₃) alkyl, (C₁ -C₈)acyloxy(C₁ -C₃)alkyl,(C₁ -C₈)alkoxymethyl and benzyloxymethyl;

R⁷ and R⁸ are independently selected from hydrogen, (C₁ -C₃)alkyl andphenyl;

R⁹ is selected from methyl, hydroxymethyl, ##STR24## R¹⁴ R¹⁵ NCO₂ CH₂--, R¹⁶ OCO₂ CH₂ --, (C₁ -C₄)alkyl--CO₂ CH₂ --, --CONR¹⁷ R¹⁸, R¹⁷ R¹⁸NCO₂ --, R¹⁹ OCO₂ --, C₆ H₅ CH₂ CO₂ CH₂ --, C₆ H₅ CO₂ CH₂ --, (C₁-C₄)alkyl--CH(OH)--, C₆ H₅ CH(OH)--, C₆ H₅ CH₂ CH(OH)--, CH₂ halo, R²⁰SO₂ OCH₂, --CO₂ R¹⁶ and R²¹ CO₂ --;

R¹⁰ and R¹¹ are independently selected from hydrogen, (C₁ -C₃) alkyl andphenyl;

R¹² is hydrogen, benzyl or a group of the formula ##STR25## wherein m isan integer from zero to twelve, and any one of the carbon-carbon singlebonds of (CH₂)_(m), wherein both carbon atoms of such bond are bonded toeach other and to another carbon atom in the (CH₃)_(m) chain, mayoptionally be replaced by a carbon-carbon double or triple bond, and anyone of the carbon atoms of (CH₂)_(m) may optionally be substituted withR²³ ;

R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹ and R²⁴ are independentlyselected from hydrogen, (C₁ -C₃)alkyl and phenyl;

R²² and R²³ are independently selected from hydrogen, hydroxy, halo,amino, carboxy, carboxy(C₁ -C₆)alkyl, (C₁ -C₆)alkylamino, di-(C₁-C₆)alkylamino, (C₁ -C₆)alkoxy, ##STR26## (C₁ -C₆) straight or branchedalkyl, (C₃ -C₇) cycloalkyl wherein one of the carbon atoms mayoptionally be replaced by nitrogen, oxygen or sulfur; aryl selected fromphenyl and naphthyl; heteroaryl selected from indanyl, thienyl, furyl,pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl,tetrazolyl and quinolyl; phenyl-(C₂ - C₆)alkyl, benzhydryl and benzyl,wherein each of said aryl and heteroaryl groups and the phenyl moietiesof said benzyl, phenyl-(C₂ -C₆)alkyl and benzhydryl may optionally besubstituted with one or two substituents independently selected fromhalo, nitro, (C₁ -C₆)alkyl optionally substituted with from one to threefluorine atoms, (C₁ -C₆)alkoxy optionally substituted with from one tothree fluorine atoms, ##STR27## and wherein one of the phenyl moietiesof said benzhydryl may optionally be replaced by naphthyl, thienyl,furyl or pyridyl;

or R⁹, together with the carbon to which it is attached, the nitrogen ofthe pyrrolidine ring, the carbon to which R⁷ is attached and the carbonto which R⁵ and R⁶ are attached form a second pyrrolidine ring; with theproviso that when R⁹, together with the carbon to which it is attached,the nitrogen of the pyrrolidine ring, the carbon to which R⁷ is attachedand the carbon to which R⁵ and R⁶ are attached, form a secondpyrrolidine ring (thus forming a bicyclic structure containing abridgehead nitrogen), either R¹² is absent or R¹² is present and thenitrogen of the second pyrrolidine ring is positively charged; or apharmaceutically acceptable salt of such compound, effective in treatingor preventing such condition.

Compounds of the formula XI that contain two pyrrolidine rings may berepresented by one of the following two structures, depending on whetherR¹² is present or absent. ##STR28## Preferred embodiments of thisinvention include methods of treating or preventing urinary incontinencein a mammal, including a human, that comprise administering to saidmammal an amount of a compound as defined in paragraphs (55) through(59) below, that is effective in treating or preventing such condition.

(55) A compound of the formula XI wherein R¹ is benzhydryl.

(56) A compound of the formula XI wherein R¹ is diphenylmethyl, R³ isaryl selected from phenyl or indanyl wherein each of said aryl groupsmay be optionally substituted with one, two or three substituents, eachof R⁵, R⁶, R⁷, R⁸, R¹⁰, and R¹¹ is hydrogen, R⁹ is selected fromhydroxymethyl, methoxymethyl, --CO₂ R¹⁶, --CONR¹⁷ R¹⁸, R¹⁴ R¹⁵ NCO₂ CH₂--, R¹⁶ OCO₂ CH₂ --, (C₁ -C₄)alkyl--CO₂ CH₂ --, C₆ H₅ CH₂ CO₂ CH₂ --,--CH₂ halo and R²⁰ SO₂ OCH₂ --, and R¹² is hydrogen or benzyl.

(57) A compound of the formula XI wherein R¹ is phenyl, R³ is arylselected from phenyl or indanyl wherein each of said aryl groups may beoptionally substituted with one, two or three substiuents, each of R⁵,R⁶, R⁷, R⁸, R¹⁰, and R¹¹ is hydrogen, R⁹ is selected from hydroxymethyl,methoxymethyl, --CO₂ R¹⁸, --CONR¹⁷ R¹⁸, R¹⁴ R¹⁵ NCO₂ CH₂ CH₂ --, R¹⁶OCO₂ CH₂ --, (C₁ -C₄) alkyl--CO₂ CH₂ --, --CH₂ halo, R²⁰ SO₂ OCH--, andR¹² is hydrogen or benzyl.

(58) A compound of the formula XI wherein R¹ is diphenylmethyl, R³ isaryl selected from phenyl or indanyl wherein each of said aryl groupsmay be optionally substituted with one, two or three substituents, eachof R⁵, R⁶, R⁷, R⁸, R¹⁰, R¹¹ and R¹³ is hydrogen, and wherein R⁹,together with the carbon to which it is attached, the nitrogen of thepyrrolidine ring, the carbon to which R⁷ is attached and the carbon towhich R⁵ and R⁶ are attached, form a second pyrrolidine ring (thusforming a bicyclic structure containing a bridgehead nitrogen).

(59) A compound of the formula XI that is selected from the groupconsisting of:

(2S, 3S,4R)-2-diphenylmethyl-3-[(2-methoxy-4,5-dimethylphenyl)methylamino]-4-(2-hydroxyethyl)pyrrolidine;

(2SR, 3SR,4RS)-2-diphenylmethyl-3-[(2-methoxy-4,5-dimethoxyphenyl)methylamino]-4-(2-hydroxyethyl)pyrrolidine;

(2SR, 3SR,4RS)-2-diphenylmethyl-3-[(2-methoxy-5-(methylethyl)phenyl)methylamino]-4-(carbomethoxymethyl)pyrrolidine;

(2SR, 3SR,4RS)-2-diphenylmethyl-3-[(2-methoxy-5-(methylethyl)phenyl)methylamino]-4-(carboxymethyl)pyrrolidine;

(2SR, 3SR,4RS)-2-diphenylmethyl-3-[(2-methoxy-5-(methylethyl)phenyl)methylamino]-4-(2-dimethylaminocarbamoylethyl)pyrrolidine;

(2SR, 3SR,4RS)-2-diphenylmethyl-3-[(2-trifluoromethoxyphenyl)methylamino]-4-(2-hydroxyethyl)pyrrolidine;

(2S, 3S,4R)-2-diphenylmethyl-3-[(2-methoxy-5-(1,1-dimethylethyl)phenyl)methylamino]-4-(2-hydroxyethyl)pyrrolidine;

(2SR, 3SR,4RS)-2-diphenylmethyl-3-[(2-methoxy-5-(1,1-dimethylethyl)phenyl)methylamino]-4-(2-methoxyethyl)pyrrolidine;

(2S, 3S,4R)-2-diphenylmethyl-3-[(2-methoxy-5-methylethyl)phenyl)methylamino]-4-(2-hydroxyethyl)pyrrolidine;

(2SR, 3SR,4RS)-2-diphenylmethyl-3-[(2-methoxy-5-methylethyl)phenyl)methylamino]-4-(2-methoxyethyl)pyrrolidine;

(2SR, 3SR,4RS)-2-diphenylmethyl-3-[(2-methyl-5-(1,1-dimethylethyl)phenyl)methylamino]-4-(2-hydroxyethyl)pyrrolidine;

(1SR, 2SR, 3SR,4RS)-1-aza-2-diphenylmethyl-3-[(2-methoxy-4,5-dimethylphenyl)-methylamino]-bicyclo[2.2.1]heptane;

(1RS, 2SR, 3SR,4RS)-1-aza-2-diphenylmethyl-3-[(2-methoxyphenyl)methylamino]bicyclo[2.2.1]heptane;

(1SR, 2SR, 3SR,4RS)-1-aza-2-diphenylmethyl-3-[(2-methoxy-5-(1,1-dimethylethyl)phenyl)methylamino]bicyclo[2.2.1]heptane;

(1SR, 2SR, 3SR,4RS)-1-aza-2-diphenylmethyl-3-[(2-methoxy-5-trifluoromethoxyphenyl)methylamino]bicyclo[2.2.1]heptane;

(1SR, 2SR, 3SR,4RS)-1-aza-2-diphenylmethyl-3-[(2-methoxy-5-(1-methoxyethyl)phenyl)methoylamino]bicyclco[2.1.1]heptane;

(1SR, 2SR, 3SR,4RS)-1-aza-2-diphenylmethyl-3-[(2-methoxy-5-propylphenyl)methylamino]bicyclo[2.2.1]heptane;

(1SR, 2SR, 3SR,4RS)-1-aza-2-diphenylmethyl-3-[(2-methoxy-5-(1-methylpropyl)phenyl)methylamino]bicyclo[2.2.1]heptane;

(1SR, 2SR, 3SR,4RS)-1-aza-2-phenyl-3-[(2-methoxyphenyl)methylamino]bicyclo[2.2.1]heptane;

(1SR, 2SR, 3RS,4RS)-1-aza-2-phenyl-3-[(2-methoxy-5-trifluoromethoxyphenyl)methylamino]bicyclo[2.2.1]heptane;

(2SR, 3SR,4RS)-N-1-phenylmethyl-2-diphenylmethyl-3-[(2-methoxyphenyl)methylamino]-4-(2-hydroxyethyl)pyrrolidine;

(2SR, 3SR,4RS)-2-diphenylmethyl-3-[(2-methoxyphenyl)methylamino]-4-(2-hydroxyethyl)pyrrolidine;

(2SR, 3SR,4RS)-2-diphenylmethyl-3[(2-methoxy-5-(1,1-dimethylethyl)phenyl)methylamino]-4-(2-hydroxyethyl)pyrrolidine;

(2SR, 3SR,4RS)-2-diphenylmethyl-3-[(2-methoxy-4-trifluoromethoxyphenyl)methylamino]-4-(2-hydroxyethyl)pyrrolidine;

(2SR, 3SR,4RS)-2-diphenylmethyl-3-[(2-methoxy-5-(1-methylethyl)phenyl)methylamino]-4-(2-hydroxyethyl)pyrrolidine;

(2SR, 3SR,4RS)-2-diphenylmethyl-3-[(2-methoxy-5-propylphenyl)methylamino]-4-(2-hydroxyethyl)pyrrolidine;

(2SR, 3SR,4RS)-2-diphenylmethyl-3-[(2-methoxy-5-(1-methyl-1-pyropyl)phenyl)methylamino]-4-(2-hydroxyethyl)pyrrolidine;

(2SR, 3SR,4RS)-2-diphenylmethyl-3-[(2-trifluoromethoxy-5-(1,1-dimethylethyl)phenyl)methylamino]-4-(2-hydroxyethyl)pyrrolidine;

(2SR, 3SR,4RS)-2-diphenylmethyl-3-[(2-methoxy-5-chlorophenyl)methylamino]-4-(2-hydroxyethyl)pyrrolidine;

(2SR, 3SR,4RS)-2-phenyl-3-[(2-methoxyphenyl)methylamino]-4-(2-hydroxyethyl)pyrrolidine;

(2SR, 3SR,4RS)-2-phenyl-3-[(2-methoxy-5-(1,1-dimethylethyl)phenyl)methylamino]-4-(2-hydroxyethyl)pyrrolidine;and

(2SR, 3SR,4RS)-2-phenyl-3-[(2-methoxy-5-trifluoromethoxyphenyl)methylamino]-4-(2-hydroxyethyl)pyrrolidine.

This invention also relates to a method of treating or preventingurinary incontinence in a mammal, including a human, comprisingadministering to said mammal an amount of a compound of the formula##STR29## wherein R¹ is hydrogen, (C₁ -C₈) alkyl, a saturated (C₆ -C₁₀)carbocyclic ring system containing two fused rings, a saturated (C₆-C₁₀) carbocyclic bridged ring system containing two rings, or benzylwherein the phenyl moiety of said benzyl may optionally be substitutedwith one or more substituents independently selected from halo, (C₁ -C₆)alkyl optionally substituted with from one to three fluorine atoms and(C₁ -C₈) alkoxy optionally substituted with from one to three fluorineatoms;

R² is hydrogen, benzyl or a group of the formula ##STR30## wherein m isan integer from zero to twelve, and any one of the carbon-carbon singlebonds of (CH₂)_(m), wherein both carbon atoms of such bond are bonded toeach other and to another carbon atom of the (CH₂)_(m) chain, mayoptionally be replaced by a carbon-carbon double or triple bond, and anyone of the carbon atoms of (CH₂)_(m) may optionally be substituted withR⁹ ;

R⁸ and R⁹ are independently selected from hydrogen, hydroxy, halo,amino, carboxy, carboxy(C₁ -C₆)alkyl, (C₁ -C₆)alkylamino, di-(C₁-C₆)alkylamino, (C₁ -C₆)alkoxy, ##STR31## (C₁ -C₆) straight or branchedalkyl, (C₃ -C₇) cycloalkyl wherein one of the carbon atoms mayoptionally be replaced by nitrogen, oxygen or sulfur; aryl selected fromphenyl and naphthyl; heteroaryl selected from indanyl, thienyl, furyl,pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl,tetrazolyl and quinolyl; phenyl-(C₂ -C₆)alkyl, benzhydryl and benzyl,wherein each of said aryl and heteroaryl groups and the phenyl moietiesof said benzyl, phenyl-(C₂ -C₆)alkyl and benzhydryl may optionally besubstituted with one or two substituents independently selected fromhalo, nitro, (C₁ -C₆)alkyl optionally substituted with from one to threefluorine atoms, (C₁ -C₆)alkoxy optionally substituted with from one tothree fluorine atoms, ##STR32## and wherein one of the phenyl moietiesof said benzhydryl may optionally be replaced by naphthyl, thienyl,furyl or pyridyl;

or R¹ and R², together with the nitrogen to which they are attached,form a saturated or unsaturated monocyclic rig containing from three toeight carbon atoms, a fused bicyclic ring containing from six to tencarbon atoms, or a saturated bridged ring system containing from six toten carbon atoms;

R⁴ is aryl selected from phenyl and naphthyl; heteroaryl selected fromindanyl, thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl,isoxazolyl, triazolyl, tetrazolyl and quinolyl; and cycloalkyl havingfrom three to seven carbon atoms wherein one of said carbon atoms mayoptionally be replaced by nitrogen, oxygen or sulfur; wherein each ofsaid aryl and heteroaryl groups may optionally be substituted with oneor more substituents, and said (C₃ -C₇) cycloalkyl may optionally besubstituted with one, two or three substituents, each of saidsubstituents being independently selected from halo, nitro, (C₁ -C₆)alkyl optionally substituted with from one to three fluorine atoms, (C₁-C₆) alkoxy optionally substituted with from one to three fluorineatoms, phenyl, ##STR33##

R³ is hydrogen, (C₃ -C₈)cycloalkyl, (C₁ -C₆) straight or branched alkylor phenyl optionally substituted with one or more substituentsindependently selected from halo, (C₁ - C₆)alkyl optionally substitutedwith from one to three fluorine atoms, and (C₁ -C₆)alkoxy optionallysubstituted with from one to three fluorine atoms;

R⁵ is hydrogen, (C₁ -C₆)alkyl, or phenyl optionally substituted with oneor more substituents independently selected from halo, (C₁ -C₆)alkyloptionally substituted with from one to three fluorine atoms and (C₁-C₆)alkoxy optionally substituted with from one to three fluorine atoms;

R⁶ is selected from hydrogen, (C₁ -C₆) straight or branched alkyl, (C₃-C₇) cycloalkyl wherein one of the carbon atoms may optionally bereplaced by nitrogen, oxygen or sulfur; aryl selected from phenyl,biphenyl, indanyl and naphthyl; heteroaryl selected from thienyl, furyl,pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl,tetrazolyl and quinolyl; phenyl (C₂ -C₆) alkyl, benzhydryl and benzyl,wherein each of said aryl and heteroaryl groups and the phenyl moietiesof said benzyl, phenyl (C₂ -C₆) alkyl and benzhydryl may optionally besubstituted with one or more substituents independently selected fromhalo, nitro, (C₁ -C₆) alkyl optionally substituted with from one tothree fluorine atoms, (C₁ -C₆) alkoxy, trifluoromethyl, amino,trihaloalkoxy (e.g., trifluoromethoxy), (C₁ -C₆)alkylamino, ##STR34##and wherein one of the phenyl moieties of said benzhydryl may optionallybe replaced by naphthyl, thienyl, furyl or pyridyl; and

R¹² is hydrogen, (C₁ -C₃)alkyl or phenyl;

or a pharmaceutically acceptable salt of such compound, that iseffective in treating or preventing such condition.

Preferred embodiments of this invention include methods of treating orpreventing urinary incontinence in a mammal, including a human, thatcomprise administering to said mammal an amount of a compound as definedin paragraphs (60) through (62) below, that is effective in treating orpreventing such condition.

(60) A compound of the formula XII wherein R² is hydrogen, or R² and R¹,together with the nitrogen to which they are attached, form a monocyclicring containing five to seven carbon atoms; R³ is hydrogen, methyl orphenyl; R⁵ is hydrogen; R⁴ is phenyl or indanyl, wherein said phenyl orindanyl may optionally be substituted with from one to threesubstituents independently selected from halo, nitro, (C₁ -C₆) alkyloptionally substituted with from one to three fluorine atoms, (C₁ -C₆)alkoxy, trihaloalkoxy (e.g., trifluoromethoxy), (C₁ -C₆) alkylamino,--C(O)NH--(C₁ -C₈)alkyl, (C₁ -C₆)alkyl--C(O)--, --C(O)--O--(C₁-C₆)alkyl, --C(O)H, --CH₂ OR¹², --NH(C₁ -C₆)alkyl, --NHC(O)H,--NHC(O)--(C₁ -C₆)alkyl, --NHSO₂ (C₁ -C₆)alkyl and (C₁ -C₆)alkyl--N--SO₂--(C₁ -C₆)alkyl; and R⁶ is phenyl.

(61) A compound of the formula XII wherein R¹ is alkyl, R⁶ isunsubstituted phenyl, R⁴ is a monosubstituted or disubstituted arylgroup that is substituted at the C-2 position with an alkoxy group orsubstituted at the C-5 position with an alkyl, alkoxy or trihaloalkoxygroup, or substituted in such manner at both C-2 and C-5 positions(i.e., with an alkoxy group at the C-2 position and an alkyl, alkoxy ortrihaloalkoxy group at the C-5 position), and each of R², R³ and R⁵ ishydrogen.

(62) A compound of the formula XII that is selected from the groupconsisting of:

1-N-cyclohexyl-1-phenyl-2-N'-[(2-methoxyphenyl)methyl]-1,2-ethanediamine;

1-N-cyclohexyl-1-phenyl-2-N'-[(2-methoxy-5-trifluoromethoxyphenyl)methyl]-1,2-ethanediamine;

1-N-pyrrolidyl-1-phenyl-2-N'-[(2-methoxyphenyl)methyl]-1,2-ethanediamine;

1-N-methyl-1-phenyl-2-N'-[(2-methoxyphenyl)methyl]-1,2-ethanediamine;

1-N-cyclopentyl-1-phenyl-2-N'-[(2-methoxyphenyl)methyl]-1,2-ethanediamine;

1-N-propyl-1-phenyl-2-N'-[(2-methoxyphenyl)methyl]-1,2-ethanediamine;

1-N-phenylmethyl-1-phenyl-2-N'-[(2-methoxyphenyl)methyl]-1,2-ethanediamine;

1-N-cyclooctyl-1-phenyl-2-N'-[(2-methoxyphenyl)methyl]-1,2-ethanediamine;

1-N-cyclobutyl-1-phenyl-2-N'-[(2-methoxyphenyl)methyl]-1,2-ethanediamine;

1-N-(2-adamantyl)-1-phenyl-2-N'-[(2-methoxyphenyl)methyl]-1,2-ethanediamine;

1-N-(1,1-dimethylethyl)-1-phenyl-2-N'-[(2-methoxyphenyl)methyl]-1,2-ethanediamine;

1-N-cyclopropyl-1-phenyl-2-N'-[(2-methoxyphenyl)methyl]-1,2-ethanediamine;

1-N-isopropyl-1-phenyl-2-N'-[(2-methoxyphenyl)methyl]-1,2-ethanediamine;

1-N-(1-phenylethyl)-1-phenyl-2-N'-[(2-methoxyphenyl)methyl]-1,2-ethanediamine;

1-N-(2-norbornyl)-1-phenyl-2-N'-[(2-methoxyphenyl)methoxyl]-1,2-ethanediamine;

1-N-cyclohexyl-1-phenyl-2-N'-[(2-methoxy-5-tert-butylphenyl)methyl]-1,2-ethanediamine;

1-N-cyclohexyl-1-phenyl-2-N'-[(2-methoxy-5-isopropylphenyl)methyl]-1,2-ethanediamine;

1-N-cyclohexyl-1-phenyl-2-N'-[(2-methoxy-4,5-dimethylphenyl)methyl]-1,2-ethanediamine;and

1-N-cyclohexyl-1-N-(6-hydroxyhexyl)-1-phenyl-2-N'-[(2-methoxyphenyl)methyl]-1,2-ethanediamine.

This invention also relates to a method of treating or preventingurinary incontinence in a mammal, including a human, comprisingadministering to said mammal an amount of a compound of the formula##STR35## wherein R¹ is cycloalkyl having from five to seven carbonatoms, pyrrolyl, thienyl, pyridyl, phenyl or substituted phenyl, whereinsaid substituted phenyl is substituted with from one to threesubstituents independently selected from fluorine, chlorine, bromine,trifluoromethyl, alkyl having from one to three carbon atoms, alkoxyhaving from one to three carbon atoms, carboxy, alkoxycarbonyl havingfrom one to three carbon atoms in the alkoxy moiety andbenzyloxycarbonyl;

R² is furyl, thienyl, pyridyl, indolyl, biphenyl, phenyl or substitutedphenyl, wherein said substituted phenyl is substituted with one or twosubstituents independently selected from fluorine, chlorine, bromine,trifluoromethyl, alkyl having from one to three carbon atoms, alkoxyhaving from one to three carbon atoms, carboxy, alkoxycarbonyl havingfrom one to three carbon atoms in the alkoxy moiety andbenzyloxycarbonyl; and

R³ is thienyl, phenyl, fluorophenyl, chlorophenyl or bromophenyl, or apharmaceutically acceptable salt of such compound, effective in treatingor preventing such condition.

Preferred embodiments of this invention include methods of treating orpreventing urinary incontinence in a mammal, including a human, thatcomprise administering to said mammal an amount of a compound as definedin paragraphs (63) through (65) below, that is effective in treating orpreventing such condition.

(63) A compound of the formula XIII, wherein R¹ is phenyl or substitutedphenyl.

(64) A compound of the formula XIII, wherein R¹ is methoxyphenyl.

(65) A compound of the formula XIII, wherein said compound is(±)-cis-9-diphenylmethyl-N-((2-methoxyphenyl)methyl)-10-azatricyclo[4.4.1.0⁵,7]undecan-8-amine.

This invention also relates to a method of treating or preventingurinary incontinence in a mammal, including a human, comprisingadministering to said mammal an amount of a compound of the formula##STR36## wherein m is an integer from 0 to 8, and any one of thecarbon-carbon single bonds of (CH₂)_(m), wherein both carbon atoms ofsuch bond are bonded to each other and to another carbon atom in the(CH₂)_(m) chain, may optionally be replaced by a carbon-carbon doublebond or a carbon-carbon triple bond, and any one of the carbon atoms ofsaid (CH₂)_(m) may optionally be substituted with R⁸ ;

w is an integer from 0 to 2;

y is an integer from 1 to 4;

z is an integer from 1 to 4, and wherein any one of the carbon atoms ofsaid (CH₂)_(z) may optionally be substituted with R⁴ ;

R¹ is hydrogen or (C₁ -C₈) alkyl optionally substituted with hydroxy,alkoxy or fluoro;

R² is a group selected from hydrogen, (C₁ -C₆) straight or branchedalkyl, (C₃ -C₇)cycloalkyl wherein one of the carbon atoms may optionallybe replaced by nitrogen, oxygen or sulfur; aryl selected from phenyl,indanyl, and naphthyl; heteroaryl selected from thienyl, furyl, pyridyl,thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl andquinolyl; phenyl(C₂ -C₆)alkyl, benzhydryl and benzyl, wherein one of thephenyl moieties of said benzhydryl may optionally be replaced bynaphthyl, thienyl, furyl or pyridyl and wherein each of said aryl andheteroaryl groups and the phenyl moieties of said benzyl, phenyl(C₂-C₆)alkyl and benzhydryl may optionally be substituted with one or moresubstituents independently selected from halo, nitro, (C₁ -C₆)alkyl, (C₁-C₆)alkoxy, trifluoromethyl, amino, (C₁ -C₆)-alkylamino, ##STR37##

R⁵ is hydrogen, phenyl or (C₁ -C₆)alkyl;

or R² and R⁵, together with the carbon to which they are attached, forma saturated carbocyclic ring having from 3 to 7 carbon atoms wherein oneof said carbon atoms may optionally be replaced by oxygen, nitrogen orsulfur;

R³ is aryl selected from phenyl, indanyl, and naphthyl; heteroarylselected from thienyl, furyl, pyridyl, thiazolyl, isothiazolyl,oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; and cycloalkylhaving 3 to 7 carbon atoms wherein one of said carbon atoms mayoptionally be replaced by nitrogen, oxygen or sulfur; wherein each ofsaid aryl and heteroaryl groups may optionally be substituted with oneor more substituents, and said (C₃ -C₇) cycloalkyl may optionally besubstituted with one or two substituents, each of said substituentsbeing independently selected from halo, nitro, (C₁ -C₆)alkyl optionallysubstituted with from one to three fluorine atoms, (C₁ -C₆)alkoxyoptionally substituted with from one to three fluorine atoms,trifluoromethyl, phenyl, amino, (C₁ -C₆)alkylamino, (C₁ -C₆)dialkylamino ##STR38##

R⁴ is independently selected from hydrogen, hydroxy, halo, amino, oxo(═O), nitrile, (C₁ -C₆)alkylamino, di-(C₁ -C₆)alkylamino, (C₁-C₆)alkoxy, ##STR39## and the groups set forth in the definition of R² ;

R⁶ is ##STR40## NHCH₂ R⁹, NHSO₂ R⁹ or one of the groups set forth in anyof the definitions of R², and R⁴ ;

R⁸ is oximino (═NOH) or one of the groups set forth in any of thedefinitions of R², and R⁴ ;

R⁹ is (C₁ -C₆)alkyl, hydrogen, phenyl or phenyl (C₁ -C₆)alkyl;

with the proviso that (a) when m is O, R⁸ is absent and R⁶ is hydrogen,(b) neither R⁴, R⁶, nor R⁸ can form, together with the carbon to whichit is attached, a ring with R⁵, (c) the sum of y and z must be less than7; or a pharmaceutically acceptable salt thereof, effective in treatingor preventing such condition.

Preferred embodiments of this invention include methods of treating orpreventing urinary incontinence in a mammal, including a human, thatcomprise administering to said mammal an amount of a compound as definedin paragraphs (66) through (68) below, that is effective in treating orpreventing such condition.

(66) A compound of the formula XIV, wherein R² is a radical selectedfrom hydrogen, phenyl, naphthyl and benzhydryl; wherein each of saidphenyl, naphthyl and benzhydryl may optionally be substituted with oneor more substituents independently selected from halo, nitro, (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, trifluoromethyl, amino, (C₁ -C₆)-alkylamino,##STR41## and wherein one of the phenyl moieties of said benzhydryl mayoptionally be replaced by naphthyl, thienyl, furyl or pyridyl.

(67) A compound of the formula XIV, wherein R² is a group selected fromhydrogen, phenyl, naphthyl and benzhydryl; wherein each of said phenyl,naphthyl and benzhydryl may optionally be substituted with one or moresubstituents independently selected from halo, nitro, (C₁ -C₆) alkyl,(C₁ -C₆) alkoxy, trifluoromethyl, amino, (C₁ -C₆)-alkylamino, ##STR42##and wherein one of the phenyl moieties of said benzhydryl may optionallybe replaced by naphthyl, thienyl, furyl or pyridyl; and

R⁴ is independently selected from hydrogen, hydroxy, halo, amino, oxo(═O), nitrile, (C₁ -C₆)alkylamino, di-(C₁ -C₆)alkylamino, (C₁-C₆)alkoxy, ##STR43## (C₁ -C₆)alkyl and phenyl.

(68) A compound of the formula XIV, wherein said compound is(3RS,4RS)-3-phenyl-4-(2-methoxybenzyl)amino-2-azabicyclo[3.3.1]nonane.

This invention also relates to a method of treating or preventingurinary incontinence in a mammal, including a human, comprisingadministering to said mammal a compound of the formula ##STR44## whereinX¹ is C₁ -C₅ alkoxy or halosubstituted (C₁ -C₅) alkoxy;

X² is hydrogen, halogen, (C₁ -C₅)alkyl, (C₂ -C₅)alkenyl, (C₂-C₅)alkynyl, (C₁ -C₅)alkoxy, (C₁ -C₅)alkylthio, (C₁ -C₅) alkylsulfinyl,(C₁ -C₅) alkylsulfonyl, halosubstituted (C₁ -C₅) alkyl, halosubstituted(C₁ -C₅) alkoxy, (C₁ -C₅)alkylamino, dialkylamino having from 1 to 5carbon atoms in each alkyl moiety, (C₁ -C₅)alkylsulfonylamino (which maybe substituted by halogen), N-(C₁ -C₅)alkyl-N-(C₁ -C₅)alkylsulfonylamino(which may be substituted by halogen in the alkylsulfonyl moiety), (C₁-C₅)alkanoylamino (which may be substituted by halogen) or N-(C₁-C₅)alkyl-N-(C₁ -C₅)alkanoylamino (which may be substituted by halogenin the alkanoyl moiety);

Ar¹ and Ar₂ are each, independently, thienyl, phenyl, fluorophenyl,chlorophenyl or bromophenyl;

A is Y--(CH₂)_(m) --CH(R²)--(CH₂)_(m) --NR¹ --;

R¹ is hydrogen, (C₁ -C₅)alkyl, benzyl or --(CH₂)_(p) --Y;

R² is hydrogen, (C₁ -C₅)alkyl (which may be substituted by a substituentselected from the group consisting of hydroxy, amino, methylthio andmercapto), benzyl, 4-hydroxybenzyl, 3-indolylmethyl or --(CH₂)_(p) --Y;

Y is --CN, --CH₂ Z or --COZ;

Z is hydroxy, amino, (C₁ -C₅)alkoxy, (C₁ -C₅) alkylamino or dialkylaminohaving from 1 to 5 carbon atoms in each alkyl moiety;

m, n and p are each, independently, 0, 1, 2 or 3; and

R¹ and R² may be connected to form a ring;

Preferred embodiments of this invention include methods of treating orpreventing urinary incontinence in a mammal, including a human, thatcomprise administering to said mammal an amount of a compound as definedin paragraph (69) below, that is effective in treating or preventingsuch condition.

(69) A compound of the formula XV, wherein said compound is selectedfrom the group consisting of:

(3R,4S,5S,6S)-N-carbamoylmethyl-5-(5-isopropyl-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxamide;

(3R,4S,5S,6S)-N-carboxymethyl-5-(5-isopropyl-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxamide;

(3R,4S,5S,6S)-3-(2-carbamoylpyrrolidin-1-yl)carbonyl-5-(5-isopropyl-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane;

(3R*,4S*,5S*,6S*)-N-(1-carbamoylethyl)-5-(5-isopropyl-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxamide;

(3R,4S,5S,6S)-N-(1-carbamoyl-3-methylbutyl)-5-(5-isopropyl-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxamide;and

(3R,4S,5S,6S)-N-(2-carbamoylethyl)-5-(5-isopropyl-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxamide.

The term "halo", as used herein, unless otherwise indicated, includeschloro, fluoro, bromo and iodo.

The term "alkyl", as used herein, unless otherwise indicated, includessaturated monovalent hydrocarbon radicals having straight, branched orcyclic moieties or combinations thereof.

The term "alkenyl", as used herein, unless otherwise indicated, refersto straight or branched hydrocarbon chain radicals having one doublebond including, but not limited to, ethenyl, 1- and 2-propenyl,2-methyl-1-propenyl, 1- and 2-butenyl.

The term "alkoxy", as used herein, unless otherwise indicated, refers to--O--alkyl, wherein alkyl is defined as above, and includes, but is notlimited to methoxy, ethoxy, propoxy, isopropy, n-butoxy, isobutoxy andt-butoxy.

The term "alkylthio", as used herein, unless otherwise indicated, refersto --S--alkyl, wherein alkyl is defined as above, and includes, but isnot limited to methylthio, ethylthio, n-propylthio, isopropylthio,n-butylthio, isobutylthio, and t-butylthio.

The term "cycloalkyl", as used herein, unless otherwise indicated,refers to cyclic hydrocarbon radicals including, but not limited tocyclopropyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term "one or more substituents," as used herein, includes from oneto the maximum number of substituents possible based on the number ofavailable bonding sites.

Compounds of the formulae I, X, XI, XII, XIII, XIV and XV contain chiralcenters and therefore exist in different enantiomeric forms. The abovedefinitions of these compounds include all optical isomers and allstereoisomers of such compounds, and mixtures thereof.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the formulae Ia, Ib, Ic, Id, X, XI, XII, XIII, and XIVmay be prepared as described below. Unless otherwise indicated, in thediscussion that follows, structural formulae Ia, Ib, Ic, Id, X, XI, XII,XIII, and XIV, and groups II, III, IV, V, VI, VII, VIII and IX aredefined as above.

Compounds of the formula Ia and Ib may be prepared as described in U.S.patent application of 988,653, which was filed on Dec. 10, 1992. Thisapplication is incorporated herein by reference in its entirety.

Compounds of the formula Ic may be prepared as described in U.S. patentapplication 932,392, which was filed on Aug. 19, 1992. This applicationis incorporated herein by reference in its entirety.

Compounds of the formula Id may be prepared as described in PCT PatentApplication PCT/US 92/03571, which designates the United States and wasfiled in the United States Receiving Office on May 5, 1992. Thisapplication is incorporated herein by reference in its entirety.

When R³ is a group of the formula II, the starting materials of theformula NH₂ R³ that are used in the preparation of compounds of theformulae Ia, Ib, Ic and Id may be prepared as described in U.S. Pat. No.5,162,339, which issued on Nov. 11, 1992. This patent is incorporatedherein by reference in its entirety.

When R³ is a group of the formula III, the starting materials of theformula NH₂ R³ that are used in the preparation of compounds of theformulae Ia, Ib, Ic and Id may be prepared as described in PCT PatentApplication PCT/US 91/02853, which designates the United States, wasfiled in the United States Receiving Office on Apr. 25, 1991 and waspublished as WO 91/18899 on Dec. 12, 1991. This application isincorporated herein by reference in its entirety.

When R³ is a group of the formula IV, V or VI, the starting materials ofthe formula NH₂ R³ that are used in the preparation of compounds of theformulae Ia, Ib, Ic and Id may be prepared as described in PCT PatentApplication PCT/US 91/03369, which designates the United States, wasfiled on in the United States Receiving Office May 14, 1991 and waspublished as WO 92/01688 on Feb. 6, 1992. This application isincorporated herein by reference in its entirety.

When R³ is a group of the formula VII, the starting materials of theformula NH₂ R³ that are used in the preparation of compounds of theformulae Ia, Ib, Ic and Id may be prepared as descried in U.S. patentapplication 724,268, filed Jul. 1, 1991, U.S. patent application800,667, filed Nov. 27, 1991 and PCT patent application PCT/US 92/00065,which designates the United States, was filed in the United StatesReceiving Office on Jan. 14, 1992 and was published as WO 92/17449 onOct. 15, 1992. These applications are incorporated herein by referencein their entirety.

When R³ is a group of the formula VIII, the starting materials of theformula NH₂ R³ that are used in the preparation of compounds of theformulae Ia, Ib, Ic and Id may be prepared as described in PCT PatentApplication PCT/US 91/05776, which designates the United States, wasfiled in the United States Receiving Office on Aug. 20, 1991 and waspublished as WO 92/06079 on Apr. 16, 1992, U.S. patent application800,667, filed Nov. 27, 1991 and PCT Patent Application PCT/US 92/00065,which designates the United States, was filed in the United StatesReceiving Office on Jan. 14, 1992 and was published as WO 92/17449 onOct. 15, 1992. These applications are incorporated herein by referencein their entirety.

When R³ is a group of the formula IX, the starting materials of theformula NH₂ R³ that are used in the preparation of compounds of theformulae Ia, Ib, Ic and Id may be prepared as described in U.S. patentapplication Ser. No. 719,884, filed Jun. 21, 1991 and PCT PatentApplication PCT/US 92/04697, which designates the United States and wasfiled in the United States Receiving Office on Jun. 11, 1992. Theseapplications are incorporated herein by reference in their entirety.

Compounds of the formula X may be prepared as described in PCT PatentApplication PCT/US 92/04002, which designates the United States, wasfiled in the United States Receiving Office on May 19, 1992 and waspublished as WO 92/15585 on Sep. 17, 1992. This application isincorporated herein by reference in its entirety.

Compounds of the formula IX may be prepared as described in PCT PatentApplication PCT/US 92/04697, which designates the United States, wasfiled in the United States Receiving Office on Jun. 11, 1992. Thisapplication is incorporated herein by reference in its entirety.

Compounds of the formula XII may be prepared as described in PCT PatentApplication PCT/US 92/07730, which designates the United States and wasfiled in the United States Receiving Office on Sep. 18, 1992. Thisapplication is incorporated herein by reference in its entirety.

Compounds of the formula XIII may be prepared as described in PCT PatentApplication PCT/US 92/06819, which designates the United States and wasfiled in the United States Receiving Office on Aug. 20, 1992. Thisapplication is incorporated herein by reference in its entirety.

Compounds of the formula XIV may be prepared as described in U.S. patentapplication 885,110, which was filed on May 18, 1992. This applicationis incorporated herein by reference in its entirety.

Compounds of the formula XV may be prepared by the procedure describedin Japanese Patent Application 065337/92, which was filed on Mar. 23,1992. These procedures are depicted in Schemes 1, 2 and 3 and discussedbelow. In the reaction schemes and discussion that follow, A, X¹, X²,Ar¹ and Ar² are defined as in the definition of compounds of the formulaXV above. ##STR45##

Referring to Scheme 1, the starting materials of the formula (i) may beprepared by the procedures described in PCT Patent Application PCT/US92/04002, which was published as WO 92/15585 on Sep. 17, 1992. Thisapplication is incorporated herein by reference in its entirety.

Introduction of a protected amino acid into a compound of the formula(i) to give a compound of the formula (ii) can be carried out by avariety of conventional methods for peptide synthesis, as described in"Peptide synthesis, the basis and experiments", edited by N. Izumiya,1985 (Maruzen).

Such methods include an activated ester method that employs an acidchloride or mixed acid anhydride, and a condensation method that employsan appropriate condensing agent selected from dicyclohexylcarbodiimide(DCC), water soluble carbodiimide,2-ethoxy-N-ethoxycarbonyl-1,2-dihydroquinoline, Bop agent,diethylcyanophosphonic acid and diphenylphospolylazide.

If necessary, addition of a tertiary amide such as triethylamine canpromote the condensation reaction. N-hydroxysuccinimide,N-hydroxybenzotriazole or3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine may be employed toprevent racemization.

Typically, a compound of the formula (ii) can be prepared from acompound of the formula (i) and an amino acid or its salt, which isprotected by an amino group or a mono- or dialkyl substituted aminogroup, by the use of a peptide coupling reagent such as DCC ordiethylcyanophosphonic acid in a reaction inert solvent such asmethylene chloride, THF or DMF, in the presence of triethylamine.

The resulting compound of the formula (ii) may be converted into acompound of the formula (iii) by reductive amination. This routeinvolves direct introduction of the appropriate benzylamino group at the3-position of the quinuclidine, and is typically conducted in two steps.In the first step, the imine formation from the compound of formula (ii)and the benzylamine is carried out by heating the reactants at thereflux temperature in a reaction inert solvent such as toluene orbenzene, in the presence of catalytic amount of acid (e.g.,p-toluenesulfonate or camphorsulfonic acid (CSA)) under dehydrolyticconditions. Alternatively, a Lewis acid such as aluminum chloride ortitanium tetrachloride can be used as the acid catalyst. Under suchcatalytic conditions, and at temperatures from about -78° C. to aboutroom temperature, it is preferable to use an acetonitrile or methylenechloride solvent together with a dehydrating agent such as molecularsieves.

In the second step, the imine is reduced to afford the compound of theformula (iii). This reduction can be carried out by either catalytichydrogenation, or by reaction with a suitable hydride reagent such as aborohydride, borane or aluminum hydride. Typically, a reagent such asNaBH₄, NaBH₃ CN or NaBH(OAc)₃ in the presence of acetic acid is used.

The above two reaction steps can be carried out simultaneously. In suchcases, the reaction is preferably carried out using NaBH₃ CN in methanolin the presence of acetic acid.

The compound of the formula (iii) can be converted into thecorresponding carboxylic of formula (iv) acid by acidic hydrolysis in aninorganic acid such as hydrochloric acid at a temperature from aboutroom temperature to about the reflux temperature for about 30 minutes toseveral hours.

The resulting carboxylic acid can be converted to the correspondingester by heating it in an alcoholic solvent in the presence of an acidcatalyst.

Alternatively, the compound of formula (iii) can be prepared by theprocedure illustrated in Scheme 2. Referring to Scheme 2, the compoundof formula (iii) can be prepared by peptide condensation from a compoundof the formula (iv) and an amino acid which is protected at its carboxylmoiety. The generic synthetic condition for various peptide syntheticmethods described in the above discussion of Scheme 1 can be used inthis reaction.

The procedure illustrated in Scheme 3 can also be used to preparecompounds of the formula (iii). Using this procedure, compounds of theformula (iii) can be prepared by reductive amination of 3-aminoquinuclidines of the formula (v) having an amino acid as the substituentA with the corresponding substituted benzaldehyde. This reductiveamination reaction proceeds easily under standard reaction conditionsbecause it goes by way of a stable imine intermediate. Use of a boranereducing agent (e.g. NaBH₃ CN or NaBH(Oac)₃ etc.) is preferred.

The starting material of formula (v) can be obtained by debenzylation ofthe compound of formula (iii). The debenzylation is preferablyaccomplished by hydrogenolysis with a palladium catalyst (e.g.,palladium or palladium hydroxide) which scarcely affects the otherfunctional groups in the compound of formula (v).

The compounds of formula (iii) prepared by the above methods can beisolated and purified by conventional procedures, such asrecrystallization or chromatography.

The compounds of the formulae Ia, Ib, Ic, Id, X, XI, XII, XIII, XIV andXV (hereinafter referred to, collectively, as the "therapeutic agents ofthis invention") and the pharmaceutically acceptable salts thereof areuseful as substance P receptor antagonists, i.e., they possess theability to antagonize the effects of tachykinins at the substance Preceptor site in mammals, and therefore they are able to function astherapeutic agents in the treatment and prevention of urinaryincontinence agents in the afflicted mammal.

The therapeutic agents of this invention that are basic in nature arecapable of forming a wide variety of different salts with variousinorganic and organic acids. Examples of acids that form suitablepharmaceutically acceptable salts for use in this invention are thosethat form non-toxic acid addition salts, i.e., salts containingpharmacologically acceptable anions, such as the hydrochloride,hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acidphosphate, acetate, lactate, citrate, acid citrate, tartrate,bitartrate, succinate, maleate, fumarate, gluconate, saccharate,benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate,p-toluenesulfonate and pamoate [i.e.,1,1'-methylene-bis-(2-hydroxy-3-naphthoate)]salts.

Although such salts must be pharmaceutically acceptable foradministration to animals, it is often desirable in practice toinitially isolate a therapeutic agent of this invention from thereaction mixture as a pharmaceutically unacceptable salt and then simplyconvert the latter back to the free base compound by treatment with analkaline reagent and subsequently convert the latter free base to apharmaceutically acceptable acid addition salt. The acid addition saltsof the base therapeutic agents of this invention are readily prepared bytreating the base compound with a substantially equivalent amount of thechosen mineral or organic acid in an aqueous solvent medium or in asuitable organic solvent, such as methanol or ethanol. Upon carefulevaporation of the solvent, the desired solid salt is readily obtained.

Those therapeutic agents of this invention that are also acidic innature are capable of forming base salts with various pharmacologicallyacceptable cations. The chemical bases that are used as reagents toprepare the pharmaceutically acceptable base salts of the therapeuticagents of this invention are those that form non-toxic base salts withthe acidic therapeutic agents of this invention. Such non-toxic basesalts include those derived from such pharmacologically acceptablecations as sodium, potassium, calcium and magnesium, etc. These saltscan easily be prepared by treating the corresponding acidic compoundswith an aqueous solution containing the desired pharmacologicallyacceptable cations, and then evaporating the resulting solution todryness, preferably under reduced pressure. Alternatively, they may alsobe prepared by mixing lower alkanolic solutions of the acidic compoundsand the desired alkali metal alkoxide together, and then evaporating theresulting solution to dryness in the same manner as before. In eithercase, stoichiometric quantities of reagents are preferably employed inorder to ensure completeness of reaction and maximum yields of thedesired final product.

The therapeutic agents of this invention and their pharmaceuticallyacceptable salts exhibit substance P receptor-binding activity andtherefore are of value in the treatment and prevention of urinaryincontinence in mammals, including humans.

The therapeutic agents of this invention and the pharmaceuticallyacceptable salts thereof can be administered via either the oral orparenteral routes. In general, these compounds are most desirablyadministered in dosages ranging from about 5.0 mg up to about 1500 mgper day, although variations will necessarily occur depending upon theweight and condition of the subject being treated and the particularroute of administration chosen. However, a dosage level that is in therange of about 0.07 mg to about 21 mg per kg of body weight per day ismost desirably employed. Variations may nevertheless occur dependingupon the species of animal being treated and its individual response tosaid medicament, as well as on the type of pharmaceutical formulationchosen and the time period and interval at which such administration iscarried out. In some instances, dosage levels below the lower limit ofthe aforesaid range may be more than adequate, while in other casesstill larger doses may be employed without causing any harmful sideeffect, provided that such larger doses are first divided into severalsmall doses for administration throughout the day.

The therapeutic agents of this invention and their pharmaceuticallyacceptable salts may be administered alone or in combination withpharmaceutically acceptable carriers or diluents by either of the threeroutes previously indicated, and such administration may be carried outin single or multiple doses. More particularly, the novel therapeuticagents of this invention can be administered in a wide variety ofdifferent dosage forms, i.e., they may be combined with variouspharmaceutically acceptable inert carriers in the form of tablets,capsules, lozenges, troches, hard candies, suppositories, aqueoussuspensions, injectable solutions, elixirs, syrups, and the like. Suchcarriers include solid diluents or fillers, sterile aqueous media andvarious non-toxic organic solvents, etc. Moreover, oral pharmaceuticalcompositions can be suitably sweetened and/or flavored. In general, thetherapeutic compounds of this invention are present in such dosage formsat concentration levels ranging from about 5.0% to about 70% by weight.

For oral administration, tablets containing various excipients such asmicrocrystalline cellulose, sodium citrate, calcium carbonate, dicalciumphosphate and glycine may be employed along with various disintegrantssuch as starch (and preferably corn, potato or tapioca starch), alginicacid and certain complex silicates, together with granulation binderslike polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally,lubricating agents such as magnesium stearate, sodium lauryl sulfate andtalc are often very useful for tabletting purposes. Solid compositionsof a similar type may also be employed as fillers in gelatin capsules;preferred materials in this connection also include lactose or milksugar as well as high molecular weight polyethylene glycols. Whenaqueous suspensions and/or elixirs are desired for oral administration,the active ingredient may be combined with various sweetening orflavoring agents, coloring matter or dyes, and, if so desired,emulsifying and/or suspending agents as well, together with suchdiluents as water, ethanol, propylene glycol, glycerin and various likecombinations thereof.

For parenteral administration, solutions of a therapeutic agent of thisinvention in either sesame or peanut oil or in aqueous propylene glycolmay be employed. The aqueous solutions should be suitably buffered ifnecessary and the liquid diluent first rendered isotonic. These aqueoussolutions are suitable for intravenous injection purposes. The oilysolutions are suitable for intraarticular, intramuscular andsubcutaneous injection purposes. The preparation of all these solutionsunder sterile conditions is readily accomplished by standardpharmaceutical techniques well known to those skilled in the art.

The activity of the therapeutic compounds of the present invention assubstance P receptor antagonists may be determined by their ability toinhibit the binding of substance P at its receptor sites in bovinecaudate tissue, employing radioactive ligands to visualize thetachykinin receptors by means of autoradiography. The substance Pantagonizing activity of the herein described compounds may be evaluatedby using the standard assay procedure described by M. A. Cascieri etal., as reported in the Journal of Biological Chemistry, Vol. 258, p.5158 (1983). This method essentially involves determining theconcentration of the individual compound required to reduce by 50% theamount of radiolabelled substance P ligands at their receptor sites insaid isolate cow tissues, thereby affording characteristic IC₅₀ valuesfor each compound tested.

In this procedure, bovine caudate tissue is removed from a -70° C.freezer and homogenized in 50 volumes (w./v.) of an ice-cold 50 mM Tris(i.e., trimethamine which is 2-amino-2-hydroxymethyl-1,3-propanediol)hydrochloride buffer having a pH of 7.7. The homogenate is centrifugedat 30,000×G for a period of 20 minutes. The pellet is resuspended in 50volumes of Tris buffer, rehomogenized and then recentrifuged at 30,000×Gfor another twenty-minute period. The pellet is then resuspended in 40volumes of ice-cold 50 mM Tris buffer (pH 7.7) containing 2 mM ofcalcium chloride, 2 mM of magnesium chloride, 4 μg/ml of bacitracin, 4μg/ml of leupeptin, 2 μg of chymostatin and 200 g/ml of bovine serumalbumin. This step completes the production of the tissue preparation.

The radioligand binding procedure is then carried out in the followingmanner, viz., by initiating the reaction via the addition of 100 μl ofthe test compound made up to a concentration of 1 μM, followed by theaddition of 100 μl of radioactive ligand made up to a finalconcentration 0.5 mM and then finally by the addition of 800 μl of thetissue preparation produced as described above. The final volume is thus1.0 ml, and the reaction mixture is next vortexed and incubated at roomtemperature (ca. 20° C.) for a period of 20 minutes. The tubes are thenfiltered using a cell harvester, and the glass fiber filters (WhatmanGF/B) are washed four times with 50 mM of Tris buffer (pH 7.7), with thefilters having previously been presoaked for a period of two hours priorto the filtering procedure. Radioactivity is then determined in a Betacounter at 53% counting efficiency, and the IC₅₀ values are calculatedby using standard statistical methods.

The ability of the therapeutic compounds of this invention to inhibitsubstance P induced effects in vivo may be determined by the followingprocedures "a" through "c". (Procedures "a" through "c" are described inNagahisa et al., European Journal of Pharmacology, 217, 191-5 (1992),which is incorporated herein by reference in its entirety.)

a. Plasma extravasation in the skin

Plasma extravasation is induced by intradermal administration ofsubstance P (50 μl, 0.01% BSA-saline solution) in dorsal skin ofpentobarbital (25 mg/kg i.p.) anesthetized male Hartley guinea pigsweighing 450-500 g. The compound to be tested is dissolved in 0.1%methyl cellulose-water (MC) and dosed p.o. 1 hour before substance Pchallenge (3 pmol/site). Evans blue dye (30 mg/kg) is administeredintravenously 5 minutes before challenge. After 10 minutes, the animalsare sacrificed, the dorsal skin is removed, and the blue spots arepunched out using a cork borer (11.5 mm oral dose (o.d.)). Tissue dyecontent is quantitated after overnight formamide extraction at 600 nmabsorbance.

b. Capsaicin-induced plasma extravasation

Plasma extravasation is induced by intraperitoneal injection ofcapsaicin (10 ml of 30 μM solution in 0.1% BSA/saline) intopentobarbital anesthetized (25 mg/kg i.p.) guinea pigs. The compound tobe tested is dissolved in 0.1% MC and dosed p.o. 1 hour before capsaicinchallenge. Evans blue dye (30 mg/kg) is administered i.v. 5 minutesbefore challenge. After 10 minutes, the animals are sacrificed, and bothright and left ureters are removed. Tissue dye content is quantitated asin "a" above.

c. Acetic acid-induced abdominal stretching

Male ddY mice (SLC, Japan), weighing 14-18 g, were fasted overnight. Thecompound to be tested is dissolved in 0.1% MC and dosed p.o. 0.5 hourbefore acetic acid (AA) injection (0.7%, 0.16 ml/10 g body weight). Theanimals are placed in clear beakers (1 per beaker) and the stretchingresponse is counted 10 to 20 minutes after the AA injection (10 minuteinterval).

We claim:
 1. A method of treating urinary incontinence in a mammal,comprising administering to said mammal an amount of a compound of theformula ##STR46## wherein A is a ring system selected from phenyl,naphthyl, thienyl, quinolinyl and indolinyl, and wherein the sidechaincontaining NR² R³ is attached to a carbon atom of ring system A;AA is anaryl group selected from phenyl, naphthyl, thienyl, dihydroquinolinyland indolinyl, and wherein the sidechain containing NR² R³ is attachedto a carbon atom of AA; W¹ is hydrogen, halo or (C₁ -C₆) alkyl, S-(C₁-C₃)alkyl, halo or (C₁ -C₆) alkoxy optionally substituted with from oneto three fluorine atoms, W is hydrogen, (C₁ -C₆)alkyl optionallysubstituted with from one to three fluorine atoms, --S(O)_(v) -(C₁ -C₆)alkyl wherein v is zero, one or two, halo or (C₁ -C₆)alkoxy optionallysubstituted with from one to three fluorine atoms; R is a 4, 5 or 6membered heterocyclic ring containing from one to three heteroatomsselected from oxygen, nitrogen and sulfur wherein said heterocyclic ringmay contain from zero to three double bonds and may optionally besubstituted with one or more substituents, independently selected from(C₁ -C₆) alkyl optionally substituted with from one to three fluorineatoms and (C₁ -C₆) alkoxy optionally substituted with from one to threefluorine atoms; R¹ is selected from amino, (C₁ -C₆)alkylamino, di-(C₁-C₆)alkylamino, --S(O)_(v) -(C₁ -C₁₀)-alkyl wherein v is zero, one ortwo, --S(O)_(v) -aryl wherein v is zero, one or two, --O-aryl, --SO₂ NR⁴R⁵ wherein each of R⁴ and R⁵ is, independently, (C₁ -C₆)alkyl, or R⁴ andR⁵, together with the nitrogen to which they are attached, form asaturated ring containing one nitrogen and from 3 to 6 carbons,##STR47## wherein one or both of the alkyl moieties may optionally besubstituted with from one to three fluorine atoms, --N(SO₂ -(C₁-C₁₀)alkyl)₂ and ##STR48## and wherein the aryl moieties of said--S(O)_(v) -aryl, --O-aryl and ##STR49## are independently selected fromphenyl and benzyl and may optionally be substituted with from one tothree substituents independently selected from (C₁ -C₄)alkyl, (C₁-C₄)alkoxy and halo; or R¹ is a group having the formula ##STR50##wherein a is 0, 1 or 2 and the asterisk represents a position meta tothe R² R³ NCH₂ side chain; the dotted lines in formula Ib represent thatone of the X-Y and Y-Z bonds may optionally be a double bond; X isselected from ═CH--, --CH₂ --, --O--, --S--, --SO--, --SO₂ --, --N(R⁴)-,--NH--, ═N--, --CH[(C₁ -C₆)alkyl]-, ═C[(C₁ -C₆)alkyl]-, --CH(C₆ H₅)- and═C(C₆ H₅)-; Y is selected from C═O, C═NR⁴, C═S, ═CH--, --CH₂ --, ═C[(C₁-C₆)alkyl]-, --CH[(C₁ -C₆)alkyl]-, ═C(C₆ H₅)-, --CH(C₆ H₅)-, ═N--,--NH--, --N(R⁴)-, ═C(halo)-, ═C(OR⁴)-, ═C(SR⁴)-, ═C(NR⁴)-, --O--, --S--and SO₂, wherein the phenyl moieties of said ═C(C₆ H₅)- and --CH(C₆ H₅)-may optionally be substituted with from one to three substituentsindependently selected from trifluoromethyl and halo, and wherein thealkyl moieties of said ═[(C₁ -C₆)alkyl]- and --CH[C₁ -C₆)alkyl]- mayoptionally be substituted with from one to three fluorine atoms; Z isselected from ═CH--, --CH₂ --, ═N--, --NH--, --S--, --N(R⁴)-, ═C(C₆H₅)-, --CH(C₆ H₅)-, ═C[(C₁ -C₆) alkyl]-and --CH[(C₁ -C₆)alkyl]-; or X, Yand Z, together with the two carbon atoms shared between the benzo ringand the XYZ ring, form a fused pyridine or pyrimidine ring; R⁴ is (C₁-C₆) alkyl or phenyl; X¹ is hydrogen, (C₁ -C₁₀) alkoxy optionallysubstituted with from one to three fluorine atoms or (C₁ -C₁₀) alkyloptionally substituted with from one to three fluorine atoms; X² and X³are independently selected from hydrogen, halo, nitro, (C₁ -C₁₀) alkyloptionally substituted with from one to three fluorine atoms, (C₁ -C₁₀)alkoxy optionally substituted with from one to three fluorine atoms,trifluoromethyl, hydroxy, phenyl, cyano, amino, (C₁ -C₆)alkylamino,di-(C₁ -C₆)alkylamino, ##STR51## R² is hydrogen or --CO₂ (C₁ -C₁₀)alkyl;R³ is selected from ##STR52## wherein R⁶ and R¹⁰ are independentlyselected from furyl, thienyl, pyridyl, indolyl, biphenyl and phenyl,wherein said phenyl may optionally be substituted with one or twosubstituents independently selected from halo, (C₁ -C₁₀) alkyloptionally substituted with from one to three fluorine atoms, (C₁ -C₁₀)alkoxy optionally substituted with from one to three fluorine atoms,carboxy, benzyloxycarbonyl and (C₁ -C₃) alkoxy-carbonyl; R⁷ is selectedfrom (C₃ -C₄) branched alkyl, (C₅ -C₆) branched alkenyl, (C₅ -C₇)cycloalkyl, and the radicals named in the definition of R⁶ ; R⁸ ishydrogen or (C₁ -C₆) alkyl; R⁹ is selected from phenyl, biphenyl,naphthyl, pyridyl, benzhydryl, thienyl and furyl, and R⁹ may optionallybe substituted with from one to three substituents independentlyselected from halo, (C₁ -C₁₀) alkyl optionally substituted with from oneto three fluorine atoms and (C₁ -C₁₀) alkoxy optionally substituted withfrom one to three fluorine atoms; Y¹ is (CH₂)_(l) wherein l is aninteger from one to three, or Y¹ is a group of the formula ##STR53## Z¹is oxygen, sulfur, amino, (C₁ -C₃)alkylamino or (CH₂)_(n) wherein n iszero, one or two; o is two; p is zero or one; R¹¹ is thienyl, biphenylor phenyl optionally substituted with one or two substituentsindependently selected from halo, (C₁ -C₁₀) alkyl optionally substitutedwith from one to three fluorine atoms and (C₁ -C₁₀) alkoxy optionallysubstituted with from one to three fluorine atoms; or a pharmaceuticallyacceptable salt thereof, effective in treating such condition.
 2. Amethod of treating urinary incontinence in a mammal, comprisingadministering to said mammal an amount of a compound having the formula##STR54## wherein W is Y or X(CH₂)_(n) ; Y is optionally substituted (C₁-C₆)alkyl, optionally substituted (C₂ -C₆)alkenyl or optionallysubstituted (C₃ -C₈)cycloalkyl;X is optionally substituted (C₁-C₆)alkoxy, CONR¹ R², CO₂ R¹, CHR¹ OR², CHR¹ NR² R³, COR¹, CONR¹ OR² oroptionally substituted aryl, wherein said aryl is selected from phenyl,naphthyl, pyridyl, quinolyl, thienyl, furyl, phenoxyphenyl, oxazolyl,tetrazolyl, thiazolyl, imidazolyl and pyrazolyl; and n is an integerfrom zero to six; Ar¹, Ar² and Ar³ are each, independently, optionallysubstituted aryl, wherein said aryl is selected from phenyl, naphthyl,pyridyl, quinolyl, thienyl, furyl, phenoxyphenyl, oxazolyl, tetrazolyl,thiazolyl, imidazolyl and pyrazolyl; and R¹, R² and R³ are independentlyselected from hydrogen, optionally substituted (C₁ -C₆)alkyl, optionallysubstituted (C₁ -C₆)alkoxy, optionally substituted (C₃ -C₈)cycloalkyl,optionally substituted aryl, wherein said aryl is selected from phenyl,naphthyl, pyridyl, quinolyl, thienyl, furyl, phenoxyphenyl, oxazolyl,tetrazolyl, thiazolyl, imidazolyl and pyrazolyl; and optionallysubstituted (C₁ -C₅)heterocyclic groups, wherein said heterocyclicgroups are selected from pyrrolidino, piperidino, morpholino,piperazinyl and thiamorpholino; and wherein the substituents on theforegoing substituted alkyl, alkenyl, cycloalkyl and alkoxy groups areindependently selected from halo, nitro, amino, (C₁ -C₄)alkyl, (C₁-C₄)alkoxy, trifluoromethyl and trifluoromethoxy; and wherein thesubstituents on the foregoing substituted heterocyclic groups areattached to an oxygen or nitrogen atom on the ring and are independentlyselected from oxygen and (C₁ -C₄)alkyl; and wherein the substituents onsaid substituted Ar¹ groups are independently selected from (C₁-C₆)alkyl optionally substituted with from one to three halo groups, (C₁-C₆)alkoxy optionally substituted with from one to three halo groups,(C₁ -C₆)alkylsulfinyl, (C₂ -C₆)alkenyl, (C₁ -C₆)alkylthio, (C₁-C₆)alkylsulfonyl, (C₁ -C₆)alkylsulfonylamino, and di-(C₁ -C₆)alkylaminowherein one or both of the alkyl groups may be optionally substitutedwith a (C₁ -C₆)alkylsulfonyl, or (C₁ -C₆)alkylsulfinyl group; andwherein the substituents on said substituted Ar² and Ar³ groups areindependently selected from (C₁ -C₄)alkyl, (C₁ -C₄)alkoxy, (C₁-C₄)alkylthio, (C₁ -C₄)alkylsulfinyl, di-(C₁ -C₄)alkylamino,trifluoromethyl and trifluoromethoxy; and wherein the substituents onsaid substituted (C₁ -C₅) heterocyclic groups are independently selectedfrom oxygen and (C₁ -C₄)alkyl; or a pharmaceutically acceptable salt ofsuch compound, effective in treating such condition.
 3. A method oftreating urinary incontinence in a mammal, comprising administering tosaid mammal an amount of a compound of the formula ##STR55## wherein R¹is cycloalkyl having from five to seven carbon atoms, pyrrolyl, thienyl,pyridyl, phenyl or substituted phenyl, wherein said substituted phenylis substituted with from one to three substituents independentlyselected from fluorine, chlorine, bromine, trifluoromethyl, alkyl havingfrom one to three carbon atoms, alkoxy having from one to three carbonatoms, carboxy, alkoxycarbonyl having from one to three carbon atoms inthe alkoxy moiety and benzyloxycarbonyl;R² is furyl, thienyl, pyridyl,indolyl, biphenyl, phenyl or substituted phenyl, wherein saidsubstituted phenyl is substituted with one or two substituentsindependently selected from fluorine, chlorine, bromine,trifluoromethyl, alkyl having from one to three carbon atoms, alkoxyhaving from one to three carbon atoms, carboxy, alkoxycarbonyl havingfrom one to three carbon atoms in the alkoxy moiety andbenzyloxycarbonyl; and R³ is thienyl, phenyl, fluorophenyl, chlorophenylor bromophenyl, or a pharmaceutically acceptable salt of such compound,effective in treating such condition.
 4. A method for treating urinaryincontinence in a mammal, comprising administering to said mammal acompound of the formula ##STR56## wherein X¹ is (C₁ -C₅) alkoxy orhalosubstituted (C₁ -C₅)alkoxy;X² is hydrogen, halogen, (C₁ -C₅)alkyl,(C₂ -C₅)alkenyl, (C₂ -C₅)alkynyl, (C₁ -C₅)alkoxy, (C₁ -C₅)alkylthio, (C₁-C₅)alkylsulfinyl, (C₁ -C₅)alkylsulfonyl, halosubstituted (C₁ -C₅)alkyl,halosubstituted (C₁ -C₅)alkoxy, (C₁ -C₅)alkylamino, dialkylamino havingfrom 1 to 5 carbon atoms in each alkyl moiety, (C₁-C₅)alkylsulfonylamino (which may be substituted by halogen), N-(C₁-C₅)alkyl-N-(C₁ -C₅)alkylsulfonylamino which may be substituted byhalogen in the alkylsulfonyl moiety, (C₁ -C₅)alkanoylamino which may besubstituted by halogen or N-(C₁ -C₅)alkyl-N-(C₁ -C₅)alkanoylamino whichmay be substituted by halogen in the alkanoyl moiety; Ar¹ and Ar₂ areeach, independently, thienyl, phenyl, fluorophenyl, chlorophenyl orbromophenyl; A is Y-(CH₂)_(m) -CH(R²)-(CH₂)_(n) -NR¹ -; R¹ is hydrogen,(C₁ -C₅)alkyl, benzyl or -(CH₂)_(p) -Y; R² is hydrogen, (C₁ -C₅)alkylwhich may be substituted by a substituent selected from the groupconsisting of hydroxy, amino, methylthio and mercapto, benzyl,4-hydroxybenzyl, 3-indolylmethyl or -(CH₂)_(p) -Y; Y is --CN, --CH₂ Z or--COZ; Z is hydroxy, amino, (C₁ -C₅)alkoxy, (C₁ -C₅)-alkylamino ordialkylamino having from 1 to 5 carbon atoms in each alkyl moiety; m, nand p are each, independently, 0, 1, 2 or 3; and R¹ and R² may beconnected to form a ring; or a pharmaceutically acceptable salt thereof,effective in treating such condition.
 5. A method of treating urinaryincontinence in a mammal, comprising administering to said mammal anamount of a compound selected from the group consistingof:(2S,3S)-N-(5-isopropyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo[2.2.2]octan-3-amine;(2S,3S)-N-(5-tert-butyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo[2.2.2]octan-3-amine;(2S,3S)-N-(5-methyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo[2.2.2]octan-3-amine;(2S,3S)-N-(5-ethyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo[2.2.2]octan-3-amine;(2S,3S)-N-(5-isopropyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo[2.2.2]octan-3-amine;(2S,3S)-N-(5-sec-butyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo[2.2.2]octan-3-amine;and(2S,3S)-N-(5-n-propyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo[2.2.2]octan-3-amine,or a pharmaceutically acceptable salt thereof, that is effective intreating such condition.
 6. A method of treating urinary incontinence ina mammal, comprising administering to said mammal an amount of acompound selected from the group consistingof:(3R,4S,5S,6S)-N,N-diethyl-5-(5-isopropyl-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxamide;(3R,4S,5S,6S)-N,N-diethyl-5-(2,5-dimethoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxamide;(3R,4S,5S,6S)-5-(5-isopropyl-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxylicacid;(3R,4S,5S,6S)-5-(2-methoxy-2-methylthiobenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxylicacid;(3R,4S,5S,6S)-5-(2,5-dimethoxybenzylamino)-6-diphenylmethyl-1-azabicyclo-[2.2.2]octane-3-carboxylicacid;(3R,4S,5S,6S)-5-(2-methoxy-5-methylbenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxylicacid;(3R,4S,5S,6S)-5-(5-ethyl-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxylicacid;(3R,4S,5S,6S)-5-(2-methoxyl-5-n-propylbenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxylicacid;(3R,4S,5S,6S)-5-(5-sec-butyl-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxylicacid;(3R,4S,5S,6S)-5-(5-aminosulfonylmethyl-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxylicacid;(3R,4S,5S,6S)-5-(2-methoxy-5-methylsulfinylbenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxylicacid;(3R,4S,5S,6S)-5-(2-methoxy-5-trifluoromethoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxylicacid;(3R,4S,5S,6S)-5-(2-methoxy-5-methylsulfonylbenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxylicacid;(3R,4S,5S,6S)-5-(5-dimethylamino-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxylicacid;(3R,4S,5S,6S)-5-(5-isopropyl-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-2-carboxylicacid;(3R,4S,5S,6S)-5-(2-methoxy-5-methylthiobenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-2-carboxylicacid;(3R,4S,5S,6S)-5-(2,5-dimethoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-2-carboxylicacid;(3R,4S,5S,6S)-5-(2-methoxy-5-methylbenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-2-carboxylicacid;(3R,4S,5S,6S)-5-(5-ethyl-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-2-carboxylicacid;(3R,4S,5S,6S)-5-(2-methoxyl-5-n-propylbenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-2-carboxylicacid;(3R,4S,5S,6S)-5-(5-sec-butyl-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-2-carboxylicacid;(3R,4S,5S,6S)-5-(5-aminosulfonylmethyl-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-2-carboxylicacid;(3R,4S,5S,6S)-5-(2-methoxy-5-methylsulfinylbenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-2-carboxylicacid;(3R,4S,5S,6S)-5-(2-methoxy-5-trifluoromethoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-2-carboxylicacid;(3R,4S,5S,6S)-5-(2-methoxy-5-methylsulfonylbenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-2-carboxylicacid; and(3R,4S,5S,6S)-5-(5-dimethylamino-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-2-carboxylicacid; or a pharmaceutically acceptable salt thereof, effective intreating such condition.